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Causal relationship between white matter structural connectivity and epilepsy.

White matter structural connectivity has recently been linked to epilepsy pathogenesis, yet its causal role remains unclear. This study used Mendelian randomization (MR) to investigate the causal relationship between white matter structural connectivity and epilepsy. GWAS summary statistics for white matter structural connectivity were sourced from the UK Biobank, while epilepsy data were obtained from FinnGen R10 and the International League Against Epilepsy (ILAE). Our MR analysis revealed significant causal links between white matter structural connectivity and epilepsy risk. Increased connectivity between the right hemisphere visual and salience/ventral attention networks (RH Vis to RH Sal/VentAttn WMSC) was associated with higher epilepsy risk in FinnGen_R10_FE_STRICT (OR&#xa0;=&#xa0;2.25, 95&#xa0;% CI&#xa0;=&#xa0;1.43-3.56, p&#xa0;<&#xa0;0.01, FDR P&#xa0;=&#xa0;0.019). Conversely, increased connectivity between left and right hemisphere salience/ventral attention networks (LH Sal/VentAttn to RH Sal/VentAttn WMSC) was linked to reduced epilepsy risk in FinnGen_R10_GE_STRICT (OR&#xa0;=&#xa0;0.17, 95&#xa0;% CI&#xa0;=&#xa0;0.07-0.46, p&#xa0;<&#xa0;0.01, FDR P&#xa0;=&#xa0;0.033). A total of 15 nominally significant associations were identified across datasets. These findings suggest a causal relationship between white matter structural connectivity and epilepsy, offering insights into disease mechanisms and potential therapeutic targets.

Humans

Maldistribution of interstitial neurons in prefrontal white matter of the brains of schizophrenic patients.

BACKGROUND: The cortical subplate is a transitory structure involved in the formation of connections in developing cerebral cortex. Interstitial neurons, normally present in subcortical white matter (WM) of the adult brain, have escaped the programmed cell death that eliminates most subplate neurons. Previous investigations indicated a maldistribution of one population of interstitial neurons in the WM of brains of schizophrenic patients, suggesting a defect of the subplate during brain development. METHODS: Three histochemically or immunocytochemically defined neuronal populations were studied in WM beneath the middle frontal gyrus of 20 schizophrenic patients and 20 matched control subjects. RESULTS: Brains of schizophrenic patients showed significant changes in the distribution of the three neuronal populations: microtubule-associated protein 2 and nonphosphorylated neurofilament-immunoreactive neurons showed a decreased density in superficial WM and an increased density in deeper WM. Nicotinamide adenine dinucleotide phosphate-diaphorase neurons were reduced in superficial WM and showed variable densities in deeper WM. Thirty-five percent of the brains of schizophrenic patients but no brains of the control subjects showed a maldistribution of neurons toward deeper WM with at least two of the three markers. Changes in neuronal distribution were not linked to age, gender, autolysis time, or subtype of schizophrenia. CONCLUSIONS: Selective displacement of interstitial WM neurons in the frontal lobe of brains of schizophrenic patients may indicate alteration in the migration of subplate neurons or in the pattern of programmed cell death. Both could lead to defective cortical circuitry in the brains of schizophrenic patients.

Adult

Neurocorrelates of nocturnal enuresis in pre-adolescent children.

INTRODUCTION: Nocturnal enuresis (NE) is a common neurodevelopmental condition, yet its underlying neural mechanisms remain unclear. This study leverages the large-scale Adolescent Brain Cognitive Development (ABCD) dataset to identify structural and functional brain correlates associated with active symptoms and the resolution of bedwetting. METHODS: Using cross-sectional data from 3472 participants aged 9-10 years, children were categorized into three groups: active nocturnal enuresis (ANE, n = 225), history of nocturnal enuresis (HNE, n = 1171), and healthy control groups (CG, n = 2076). Multimodal neuroimaging protocol evaluated macrostructural properties via structural MRI (sMRI), microstructural white matter integrity via diffusion MRI (dMRI), and functional connectivity via resting-state fMRI (fMRI). Group differences were evaluated using linear models within an ANCOVA framework, adjusting for intracranial volume and handedness with False Discovery Rate (FDR) correction. RESULTS: Compared to controls, the ANE group exhibited a significant volume deficit in the right caudate, decreased sulcal depth in the left insula, and lower internal correlation within the Cingulo-Opercular Network (CON). Conversely, the dry HNE group demonstrated significant structural adaptations, including bilaterally larger putamen volumes and increased right caudate volume compared to the ANE group. The HNE group also showed increased microstructural density (decreased mean diffusivity) in the bilateral hippocampus and an increased cortical surface area in the left insula. Both NE groups demonstrated persistently reduced functional coupling within the CON. CONCLUSIONS: Nocturnal enuresis appears to be associated with a potential complex central signaling deficits. Reduced internal correlation within the CON across both active and former bedwetters indicates a potential for impairment in processing internal homeostatic bladder signals during sleep.

Humans

Neuronal ectopic masses induced by prenatal irradiation in the rat.

Ectopic neuronal masses below the subcortical white matter were seen in the brains of postnatal rats after 200 cGy irradiation at embryonic day 14. In contrast with the laminated organisation of the cortex located above the subcortical white matter, the ectopic masses were formed of confluent nodules composed of pyramidal and non-pyramidal neurons distributed at random, with no laminar organisation. Afferent and efferent fibres to/from the ectopic masses running together with fibres passing the subcortical white matter indicated that the ectopic masses were heavily connected to neighbouring structures. Examination of irradiated embryos revealed that the ectopic masses originated from ectopic periventricular rosettes, composed of germinal cells, which were formed shortly after irradiation. Neuronogenesis in these rosettes did not follow an inside-out gradient, as seen in the laminated cortex; however, early-generated neurons predominated in the external regions, whereas late-generated neurons were mainly located in the middle and internal regions of the ectopic masses.

Animals

Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development.

Epidemiological and anatomical studies support the theory that disturbances of brain development may play a contributory role in the etiology of schizophrenia. Anatomical findings suggest that the normal pattern of neuronal migration during development of the cerebral cortex may be affected in the brains of schizophrenics, with the implication that cortical connectivity and associative function will be disrupted. In the present investigation in matched schizophrenic and control brains, we examined a particular population of neurons found in the prefrontal cortex and underlying white matter and characterized by histochemical staining for the enzyme nicotinamide-adenine dinucleotide phosphate-diaphorase. In normal brains, these neurons are found in highest numbers in the white matter immediately deep to layer VI of the cortex where they remain from the subplate, an early formed, but transitory structure that plays a key role in cortical development and connection formation. The dorsolateral prefrontal area of schizophrenics showed a significant decline in nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in the superficial white matter and in the overlying cortex but a significant increase in these neurons in white matter deeper than 3 mm from the cortex. These findings are consistent with a disturbance of the subplate during development in which the normal pattern of programmed cell death is compromised and accompanied by a defect in the normal orderly migration of neurons toward the cortical plate. These are likely to have serious consequences for the establishment of a normal pattern of cortical connections leading to a potential breakdown of frontal lobe function in schizophrenics.

Adult

Dysmodularity: a neurocognitive model for schizophrenia.

Hoffman and McGlashan's introduction of the term neurodynamics prompts a neurocognitive account of schizophrenia along the same lines, called "dysmodularity." In cognitive terms dysmodularity describes an impairment in the function of specialized processors due to a breakdown in one of their prime attributes: informational encapsulation. In neural terms dysmodularity implies increased structural and functional connectivity, reduced anatomical specialization such as lateral asymmetries, and increased white matter in relation to gray. Reduced cortical pruning would be one mechanism for dysmodularity. This model is opposite to the excessive pruning model proposed by Hoffman and McGlashan, but we believe it is more firmly supported by the literature, including some articles in the same issue of Schizophrenia Bulletin (Vol. 19, No. 1, 1993).

Attention

Localization of atrophy-prone areas in the aging mouse brain: comparison between the brain atrophy model SAM-P/10 and the normal control SAM-R/1.

Mouse inbred strain "SAM-P/10" (Senescence Accelerated Mouse) is a model of age-related brain atrophy. In this strain there is an earlier and more severe age-related deterioration in the conditional avoidance learning than the normal control inbred SAM-R/1 strain. The present study analysed age-related changes in brain area size using a computerized morphometric method. The region most vulnerable to age-related atrophy in SAM-P/10 was the frontal region of the cerebral cortex, including the prefrontal cortex. Other neocortical regions underwent diffuse atrophy. Posterior piriform cortex, entorhinal cortex, anterior olfactory nucleus, amygdala, caudate-putamen, nucleus accumbens and cerebellar cortex were atrophy-prone regions. The septum also underwent atrophy but other basal forebrain structures were intact. The hippocampus, diencephalon and brainstem structures showed no atrophic change. White matter structures did not change in size with aging except for the forceps minor of the corpus callosum, which showed age-related atrophy. On the contrary, SAM-R/1 showed a significant age-related atrophy only in a restricted part of the cerebral cortex, mainly in the parietal region. Other cortical regions, subcortical structures, diencephalon, brainstem structures, cerebellum and white matter were atrophy-resistant in SAM-R/1. The prefrontal cortex, entorhinal cortex, piriform cortex and striatum are closely interconnected and also connect with the amygdala which plays a key role in conditioning in the rodent. Age-related atrophy in all these structures in SAM-P/10 presumably accounts for the age-related deficits in conditional avoidance learning in this strain of mouse. Comparison between SAM-P/10 and SAM-R/1 or other well-known rodents indicates that SAM-P/10 is a unique rodent that spontaneously and rapidly develops progressive generalized cerebral atrophy, which is considered to be a pathological process rather than an accelerated aging process.

Aging

Periodic EEG patterns observed in two cases with partial seizures.

Two cases with partial seizure and periodic EEG pattern were reported. Case 1. A 74-year-old woman reveal typical periodic lateralized epileptiform discharges (PLED's) on the right hemisphere. The patient was semicomatous with mild jaundice and epilepsia partialis continua in the left lower limb. Postmortem examination revealed a main metastatic carcinoma of pancreas head origin in the right parietooccipital region. In the right hemisphere, the cortical structures were relatively preserved, but the white matter including the frontal lobe was swollen and its demyelinating changes were observed diffusely. The PLED's might result from an anatomical or functional severance of the cerebral cortex from normal connections with deeper structures. Case 2. A 61-year-old woman, with idiopathic hypoparathyroidism showed partial complex seizure. The EEG revealed an anterior temporal spike focus and slowing in the right hemisphere, corresponding with repetitive seizures of about one minute duration and with several minutes interval. An interictal periodic EEG pattern appeared in the right anterior and mid-temporal region. No cerebral abnormalities were found with other neurological examinations including brain scanning, carotisangiogram, and echoencephalogram. The periodic pattern was assumed as subclinical focal seizure discharges from the right anterior temporal deep structures.

Aged

The anatomy of mood disorders--review of structural neuroimaging studies.

The structural neuroimaging findings in mood disorders were reviewed, to evaluate evidence for a neuroanatomic model of pathophysiology, involving the prefrontal cortex, the basal ganglia, the amygdala-hippocampus complex, thalamus, and connections among these structures. Global atrophy is not consistently found. The best replicated finding is an increased rate of white matter and periventricular hyperintensities. A smaller frontal lobe, cerebellum, caudate, and putamen appear present in unipolar depression. A larger third ventricle, and smaller cerebellum and perhaps temporal lobe appear present in bipolar disorder. These localized structural changes involve regions that may be critical in the pathogenesis of mood disorders. Generalized and localized anatomic alterations may be related to age or vascular disease. The clinical and biological correlates of these changes need to be investigated to allow development of a more complete model of pathophysiology of mood disorders.

Atrophy

[Antigenic similarity between stimulators of immunogenesis of a polypeptide nature from the thymus and cerebral cortex].

Rabbit antisera against low molecular weight polypeptides from the thymus (thymosin and thymarin), cortex (cortexin) and white matter of the brain of the calves were cross-absorbed with these polypeptides and tested in the complement fixation test with these preparations and in the complement-dependent cytotoxicity test with thymic and bone marrow cells. The results showed that thymosin, thymarin and cortexin are antigenically similar, but differ in antigenic structure from polypeptide from white matter of the brain. Biological effect of polypeptides from the thymus and brain cortex is connected with thymus-depending lymphocytes and does not depend on B-cells. Cross absorbtion revealed that antisera against polypeptides from thymus and cortex of the brain contain antibody both against common antigens and antigens specific for appropriate preparation only. Antigenic set of polypeptide from the thymus (thymarin) corresponds more closely to thymic antigen as compared to polypeptide from the brain cortex (cortexin).

Adjuvants, Immunologic

[Nasal cerebral heterotopic tissue (nasal glioma) in the adult: a rare cause of primary cerebrospinal fluid rhinorrhea].

BACKGROUND: Nasal cerebral heterotopia is a congenital lesion that is mainly detected in early childhood. The rare cases of this disorder found in adult patients are located intranasally. A common symptom is compromised nasal air passage. Clinical findings include polypoid masses in either the nasal cavity or the paranasal sinuses. To our knowledge, primary cerebrospinal fluid (CSF) rhinorrhea has been reported only twice in these patients. PATIENT: A 64-year-old female patient presented with CSF rhinorrhea proven by beta 2-transferrin testing. Previous head injury or intranasal manipulation were excluded. Anterior rhinoscopy revealed a watery drainage from the right middle meatus. CT scan showed a defect in the lateral roof of the right ethmoid sinus, approximately 5 mm in diameter; MRI revealed a mass in the right ethmoid and frontal sinuses, penetrating the anterior skull base. The lesion was resected by an extranasal approach. It showed a fibrous connection to the frontal lobe. Histologically, the lesion consisted of neural tissue composed of gray and white matter, both with a normal structuring. Dura and skull base were reconstructed. There were no signs of a CSF leak postoperatively. RESULTS AND CONCLUSIONS: The differential diagnosis of CSF rhinorrhea includes traumatic events and neoplasms, elevated intracranial pressure, and connate lesions as encephaloceles and, in rare cases, nasal cerebral heterotopia.

Adult

Marked retrograde and anterograde amnesia of a visual discrimination task in rats with selective lesions of the perirhinal cortex.

Damage to the temporal cortex (TC), the lateral entorhinal cortex (LEC), or their interconnections has disruptive effects on visual memory. The fiber connections between TC and LEC are relayed in the perirhinal cortex (PC) or in the adjacent white matter of PC. PC seems to make up a particularly important structure for mnemonic processing. The purpose of the present study was to examine whether selective PC lesions might affect retroactive or proactive memory, since TC/LEC transections can cause both retrograde and anterograde amnesia. The results show that both PC and TC/LEC lesions impair retroactive memory to similar degrees (Experiment 1). However, PC lesions yielded a slightly stronger impairment of both acquisition and retention in the proactive paradigm than TC/LEC lesions (Experiment 2). These findings give support to the notion that PC plays an important role in formation of memory.

Amnesia

Myeloarchitecture of the cerebellum of the chicken (Gallus domesticus): an atlas of the compartmental subdivision of the cerebellar white matter.

A myeloarchitectonic atlas of the longitudinal (or mediolateral) subdivision of the cerebellum of the chicken (white Leghorn) was prepared from serial Häggqvist or toluidine-blue-stained sections of five animals. This myeloarchitectonic subdivision is based on the alternate occurrence of large fiber accumulations (LFAs) and small fiber areas (SFAs) in the cerebellar white matter and allows the distinction of a number of parasagittal fiber compartments, each of which consists of a medial LFA and a lateral SFA. The compartmental subdivision of the cerebellar white matter in mammals and birds derives its importance from the fact that essentially it corresponds to the organization of the afferent and efferent connections of the cerebellar cortex. The simple structure of the avian cerebellum makes it ideally suited for a complete description of its compartmental subdivision and may serve as a natural system of coordinates in future anatomical and physiological studies. The number of fiber compartments that can be counted in the chicken cerebellum on either side of the midline varies from six (in the narrowest folium I) to nine (in the widest folia IX and X) and is approximately the same as in mammals, in which a maximum of eight or ten compartments can be recognized. On the basis of the organization of its myeloarchitecture and the otherwise relatively scarce data on the organization of the connections of its cortex, it can, therefore, be postulated that the avian cerebellum is the homologue of the entire mammalian cerebellum. In addition, the present knowledge of the connections of the cerebellar cortex in birds indicates that the avian compartments 1-3 may correspond to the mammalian compartments A1, A2, and A3 (or X), whereas the avian compartment 4 or 5 (or both) may represent the mammalian B compartment. Lack of further anatomical data so far precludes conclusions on a possible homology between the avian compartments 6-9 and the mammalian C and D compartments.

Animals

The effects of aging on area 46 of the frontal cortex of the rhesus monkey.

An examination of cortex of area 46 in the floor of the principal sulcus in the frontal lobe of the rhesus monkey has been carried out using three young (4-6 years of age), one middle-aged (12 years of age), and five old (25-32 years of age) rhesus monkeys. Light microscopic examination revealed no age-related change in the thickness of the cortex, and no changes in the frequency of profiles of neurons displaying nuclei and contained in 250-micron-wide strips of 1-micron-thick sections. Since the diameters of the nuclei of the neurons were found to be the same in the young and old monkeys, it was concluded that there was no change in the numbers of neurons beneath similar areas of cortical surface of area 46 with age. This conclusion was reinforced by an electron microscopic examination, since there was no suggestion of degeneration of the cell bodies of the neurons, which accumulated but little lipofuscin in the old monkeys. However, there were signs of degeneration in some of the dendrites in the upper layers of the cortex in the old monkeys, especially in layer 1, in which many of the dendrites had lost organelles from their cytoplasm. The other notable change was a degeneration of myelinated axons in the deep layers and white matter in some of the old monkeys. In contrast to the neurons, the effects of aging on the neuroglial cells and pericytes were very obvious, since in the old monkeys each type of neuroglial cell accumulated large inclusions within its cytoplasm. Prior to fixation, these monkeys had been behaviorally tested using a series of spatial and visual recognition tasks, which revealed that relative to the young monkeys, the old monkeys as a group displayed memory impairment. On one task, the extent of the impairment for each old monkey correlated well with the extent of degeneration of myelinated fibers in the cortex and white matter. Consequently, it is suggested that age-related cognitive changes are unlikely to be a result of a loss of neurons, but might be due to an alteration in connections between the cortex and other brain structures.

Aging

Pathology of subcortical visual centres in relation to cortical degeneration in Alzheimer's disease.

Subcortical visual centres such as the lateral geniculate nucleus, the lateral inferior pulvinar and the superior colliculus, together with the primary visual cortex and its adjacent white matter, were studied in 12 Alzheimer brains and five age-matched controls. The periodic acid methenamine technique was used for the demonstration of senile plaques and the Gallyas technique for neurofibrillary tangles and neuritic threads in the neuropil. In the lateral geniculate nucleus and inferior pulvinar, the presence of periodic acid methenamine-positive senile plaques was observed in variable numbers in all Alzheimer cases. In the lateral geniculate nucleus, senile plaques were encountered more often in parvocellular than in magnocellular layers, in the interlaminar zones, in the optic radiation and in the adjacent pre-geniculate nucleus. Gallyas staining did not reveal any neurofibrillary tangles, neuritic threads or neuritic plaques, meaning that in this thalamic region there are mainly amyloid deposits without neuritic degeneration. In the superior colliculus both amyloid and neuritic plaques, as well as neurofibrillary tangles and neuritic threads were encountered in the superficial and deep layers. In the primary visual cortex, all types of senile plaques were observed as well as a rather high number of neurofibrillary lesions in pyramidal neurons, mainly in layers 5 and 6, but also in several types of non-pyramidal neurons. In the underlying white matter there was a morphologically heterogeneous population of neurofibrillary tangle-bearing neurons and a considerable number of threads representing degenerating axons, suggesting that degeneration could follow corticosubcortical connections. These data demonstrate that lesions in the primary visual structures and pathways are more prevalent than previously observed and could partly explain the visual disturbances in Alzheimer's disease.

Aged

Examining the volume efficiency of the cortical architecture in a multi-processor network model.

The convoluted form of the sheet-like mammalian cortex naturally raises the question whether there is a simple geometrical reason for the prevalence of cortical architecture in the brains of higher vertebrates. Addressing this question, we present a formal analysis of the volume occupied by a massively connected network or processors (neurons) and then consider the pertaining cortical data. Three gross macroscopic features of cortical organization are examined: the segregation of white and gray matter, the circumferential organization of the gray matter around the white matter, and the folded cortical structure. Our results testify to the efficiency of cortical architecture.

Animals

An effect of structured backgrounds on smooth pursuit eye movements in patients with cerebral lesions.

The oculomotor smooth pursuit system is driven by the slip of the target image upon the retina arising from errors in matching eye and target velocities. However, pursuit of an object moving against a structured background causes most retinal flow to be in the direction opposite to target movement. Central mechanisms allow these distracting signals to be overridden effortlessly. To isolate the anatomical substrate of this capacity we studied the effect of the presence of a structured background upon smooth pursuit in 26 patients with focal cerebral lesions. In normal control subjects, studies confirmed that a background has little effect upon pursuit. Eye movements were recorded by the scleral search coil method or by infra-red oculography. The target was a bright spot moving horizontally in a triangular waveform of amplitude +/- 11.25 degrees visual angle, at either 10, 20, 30 or 36.5 degrees/s. Data were collected in darkness and with a structured background: 14 patients showed a significant reduction of gain with a structured background, while the remaining 12 showed little or no effect. Comparison of the location of the cerebral lesions in these two groups suggested that lesions in the inferior parietal cortex (area 40) or in white matter containing parieto-frontal connections result in disruption of pursuit in the presence of a background.

Adult

[Congenital muscular dystrophy associated with micropolygyria of the cerebrum and cerebellum].

The characteristic features of micropolygyria were demonstrated in the cerebral and cerebellar gray matter of two cases, 5 and 16 years old males, of congenital muscular dystrophy. (Fokuyama type). The micropolygyria of the cerebral cortex showed an undifferentiated cytoarchitecture, e. g. status verrucosus deformis. On the surface of cortical molecular layer, subpial mesenchymal fibres, tangential myelin fibres and marginal glial fibres were observed to be still proliferated even at the stages examined and all the fibres were caved into the cortical cell layer associated with the molecular layer, without secondary sulcus formation. It is proposed that micropolygyria without secondary sulcus formation described in the present paper is named as "pachygyric micropolygyria", while four-layered type of micropolygyria with normal sulcus formation is "eugyric micropolygyria". On the other hand, micropolygyria of the cerebellar cortex was found to be consisted of various sized fragments in which basic structures of the cerebellum were preserved. On a part of surface of the cerebellar cortex the cytoarchitecture of cell layers was shown in inverse order. The Purkinje cell were irregularly migrated and the external granular layer remained in the molecular layer showing ectopic features. Tangential myelin fibres, connecting with fibres of the folial white matter, were observed to exist on the surface of the internal granular layer.

Adolescent