The temporal lobes play a prominent role in declarative memory function, including episodic memory (memory for events) and semantic memory (memory for facts and concepts). Surgical resection for medication-resistant and well-localized temporal lobe epilepsy has good prognosis for seizure freedom, but is linked to memory difficulties in adults, especially when the removal is on the left side. Children may benefit most from surgery, because brain plasticity may facilitate post-surgical reorganization, and seizure cessation may promote cognitive development. However, the long-term impact of this intervention in children is not known. We examined memory function in 53 children (25 males, 28 females) who were evaluated for epilepsy surgery: 42 underwent unilateral temporal lobe resections (25 left, 17 right, mean age at surgery 13.8 years), 11 were treated only pharmacologically. Average follow-up was 9 years (range 5-15). Post-surgical change in visual and verbal episodic memory, and semantic memory at follow-up were examined. Pre- and post-surgical T1-weighted MRI brain scans were analysed to extract hippocampal and resection volumes, and evaluate post-surgical temporal lobe integrity. Language lateralization indices were derived from functional magnetic resonance imaging. There were no significant pre- to postoperative decrements in memory associated with surgery. In contrast, gains in verbal episodic memory were seen after right temporal lobe surgery, and visual episodic memory improved after left temporal lobe surgery, indicating a functional release in the unoperated temporal lobe after seizure reduction or cessation. Pre- to post-surgical change in memory function was not associated with any indices of brain structure derived from MRI. However, better verbal memory at follow-up was linked to greater post-surgical residual hippocampal volumes, most robustly in left surgical participants. Better semantic memory at follow-up was associated with smaller resection volumes and greater temporal pole integrity after left temporal surgery. Results were independent of post-surgical intellectual function and language lateralization. Our findings indicate post-surgical, hemisphere-dependent material-specific improvement in memory functions in the intact temporal lobe. However, outcome was linked to the anatomical integrity of the temporal lobe memory system, indicating that compensatory mechanisms are constrained by the amount of tissue which remains in the operated temporal lobe. Careful tailoring of resections for children undergoing epilepsy surgery may enhance long-term memory outcome.
A general consensus is emerging that the hippocampus has an important and active role in the creation of new long-term memory representations of associations or bindings between elements. However, it is less clear whether this contribution can be extended to the creation of temporary bound representations in working memory, involving the retention of small numbers of items over short delays. We examined this by administering a series of recognition and recall tests of working memory for colour-location binding and object-location binding to a patient with highly selective hippocampal damage (Jon), and groups of control participants. Jon achieved high levels of accuracy in all working memory tests of recognition and recall binding across retention intervals of up to 10s. In contrast, Jon performed at chance on an unexpected delayed test of the same object-location binding information. These findings indicate a clear dissociation between working memory and long-term memory, with no evidence for a critical hippocampal contribution to item-location binding in working memory.
Neonates treated for acute respiratory failure experience episodes of hypoxia. The hippocampus, a structure essential for memory, is particularly vulnerable to such insults. Hence, some neonates undergoing treatment for acute respiratory failure might sustain bilateral hippocampal pathology early in life and memory problems later in childhood. We investigated this possibility in a cohort of 40 children who had been treated neonatally for acute respiratory failure but were free of overt neurological impairment. The cohort had mean hippocampal volumes (HVs) significantly below normal control values, memory scores significantly below the standard population means, and memory quotients significantly below those predicted by their full scale IQs. Brain white matter volume also fell below the volume of the controls, but brain gray matter volumes and scores on nonmnemonic neuropsychological tests were within the normal range. Stepwise linear regression models revealed that the cohorts HVs were predictive of degree of memory impairment, and gestational age at treatment was predictive of HVs: the younger the age, the greater the atrophy. We conclude that many neonates treated for acute respiratory failure sustain significant hippocampal atrophy as a result of the associated hypoxia and, consequently, show deficient memory later in life.
Reorganization of eloquent cortex enables rescue of language functions in patients who sustain brain injury. Individuals with left-sided, early-onset focal epilepsy often show atypical (i.e. bilateral or right-sided) language dominance. Surprisingly, many patients fail to show such interhemispheric shift of language despite having major epileptogenic lesions in close proximity to eloquent cortex. Although a number of epilepsy-related factors may promote interhemispheric plasticity, it has remained unexplored if neuroanatomical asymmetries linked to human language dominance modify the likelihood of atypical lateralization. Here we examined the asymmetry of the planum temporale, one of the most striking asymmetries in the human brain, in relation to language lateralization in children with left-sided focal epilepsy. Language functional magnetic resonance imaging was performed in 51 children with focal epilepsy and left-sided lesions and 36 healthy control subjects. We examined the association of language laterality with a range of potential clinical predictors and the asymmetry of the length of the planum temporale. Using voxel-based methods, we sought to determine the effect of lesion location (in the affected left hemisphere) and grey matter density (in the unaffected right hemisphere) on language laterality. Atypical language lateralization was observed in 19 patients (38%) and in four controls (11%). Language laterality was increasingly right-sided in patients who showed atypical handedness, a left perisylvian ictal electroencephalographic focus, and a lesion in left anterior superior temporal or inferior frontal regions. Most striking was the relationship between rightward asymmetry of the planum temporale and atypical language (R = 0.70, P < 0.0001); patients with a longer planum temporale in the right (unaffected) hemisphere were more likely to have atypical language dominance. Voxel-based regression analysis confirmed that increased grey matter density in the right temporo-parietal junction was correlated with right hemisphere lateralization of language. The length of the planum temporale in the right hemisphere was the main predictor of language lateralization in the epilepsy group, accounting for 48% of variance, with handedness accounting for only a further 5%. There was no correlation between language lateralization and planum temporale asymmetry in the control group. We conclude that asymmetry of the planum temporale may be unrelated to language lateralization in healthy individuals, but the size of the right, contra-lesional planum temporale region may reflect a reserve capacity for interhemispheric language reorganization in the presence of a seizure focus and lesions within left perisylvian regions.
Amnesic patients with bilateral hippocampal damage sustained in adulthood are generally unable to construct scenes in their imagination. By contrast, patients with developmental amnesia (DA), where hippocampal damage was acquired early in life, have preserved performance on this task, although the reason for this sparing is unclear. One possibility is that residual function in remnant hippocampal tissue is sufficient to support basic scene construction in DA. Such a situation was found in the one amnesic patient with adult-acquired hippocampal damage (P01) who could also construct scenes. Alternatively, DA patients scene construction might not depend on the hippocampus, perhaps being instead reliant on non-hippocampal regions and mediated by semantic knowledge. To adjudicate between these two possibilities, we examined scene construction during functional MRI (fMRI) in Jon, a well-characterised patient with DA who has previously been shown to have preserved scene construction. We found that when Jon constructed scenes he activated many of the regions known to be associated with imagining scenes in control participants including ventromedial prefrontal cortex, posterior cingulate, retrosplenial and posterior parietal cortices. Critically, however, activity was not increased in Jons remnant hippocampal tissue. Direct comparisons with a group of control participants and patient P01, confirmed that they activated their right hippocampus more than Jon. Our results show that a type of non-hippocampal dependent scene construction is possible and occurs in DA, perhaps mediated by semantic memory, which does not appear to involve the vivid visualisation of imagined scenes.
The optic radiation (OR) is a component of the visual system known to be myelin mature very early in life. Diffusion tensor imaging (DTI) and its unique ability to reconstruct the OR in vivo were used to study structural maturation through analysis of DTI metrics in a cohort of 90 children aged 5-18 years. As the OR is at risk of damage during epilepsy surgery, we measured its position relative to characteristic anatomical landmarks. Anatomical distances, DTI metrics and volume of the OR were investigated for age, gender and hemisphere effects. We observed changes in DTI metrics with age comparable to known trajectories in other white matter tracts. Left lateralization of DTI metrics was observed that showed a gender effect in lateralization. Sexual dimorphism of DTI metrics in the right hemisphere was also found. With respect to OR dimensions, volume was shown to be right lateralised and sexual dimorphism demonstrated for the extent of the left OR. The anatomical results presented for the OR have potentially important applications for neurosurgical planning.
Thyroid hormones exert their effects through alpha (TR?1) and beta (TR?1 and TR?2) receptors. Here we describe a child with classic features of hypothyroidism (growth retardation, developmental retardation, skeletal dysplasia, and severe constipation) but only borderline-abnormal thyroid hormone levels. Using whole-exome sequencing, we identified a de novo heterozygous nonsense mutation in a gene encoding thyroid hormone receptor alpha (THRA) and generating a mutant protein that inhibits wild-type receptor action in a dominant negative manner. Our observations are consistent with defective human TR?-mediated thyroid hormone resistance and substantiate the concept of hormone action through distinct receptor subtypes in different target tissues.
The present study aims to describe the cognitive profile of children with medically refractory extratemporal epilepsies who undergo focal surgery and to identify determinants for preoperative and postoperative cognitive level.
The white matter of the brain undergoes a range of structural changes throughout development; from conception to birth, in infancy, and onwards through childhood and adolescence. Several studies have used diffusion magnetic resonance imaging (dMRI) to investigate these changes, but a consensus has not yet emerged on which white matter tracts undergo changes in the later stages of development or what the most important driving factors are behind these changes. In this study of typically developing 8- to 16-year-old children, we use a comprehensive data-driven approach based on principal components analysis to identify effects of age, gender, and brain volume on dMRI parameters, as well as their relative importance. We also show that secondary components of these parameters predict full-scale IQ, independently of the age- and gender-related effects. This overarching assessment of the common factors and gender differences in normal white matter tract development will help to advance understanding of this process in late childhood and adolescence.
The MRC UKALLXI trial tested the efficacy of different central nervous system (CNS) directed therapies in childhood acute lymphoblastic leukaemia (ALL). To evaluate morbidity 555/1826 randomised children underwent prospective psychological evaluations. Full Scale, verbal and performance IQs were measured at 5 months, 3 years and 5 years. Scores were compared in; (1) all patients (n = 555) versus related controls (n = 311), (2) low-risk children (presenting white cell count (WCC) < 50 × 10(9)/l) randomised to intrathecal methotrexate (n = 197) versus intrathecal and high-dose intravenous methotrexate (HDM) (n = 202), and (3) high-risk children (WCC ? 50 × 10(9)/l, age ? 2 years) randomised to HDM (n = 79) versus cranial irradiation (n = 77).
This study investigated the role of underlying pathology on memory function of children with temporal lobe epilepsy (TLE). Memory was assessed in 44 children with TLE resulting from hippocampal sclerosis (HS) or dysembryoplastic neuroepithelial tumours (DNT), and 22 control children. Delayed story and paired associate recall performance was significantly more impaired in children with HS compared to those with DNT, irrespective of the affected side. Semantic memory was impaired in both HS groups, and also in the left DNT group. These results suggest a role for type, and to a lesser extent, side of pathology in the memory profile of children with TLE.
A number of studies suggest an important role for the hippocampus in tasks involving visuospatial or relational working memory. We test the generality of this proposal across tasks using a battery designed to investigate the various components of working memory, studying the working memory performance of Jon, who shows a bilateral reduction in hippocampal volume of approximately 50%, comparing him to a group of 48 college students. We measure performance on four complex working memory span measures based on combining visuospatial and verbal storage with visuospatial or verbal concurrent processing as well as measuring Jons ability to carry out the component storage and processing aspects of these tasks. Jon performed at a consistently high level across our range of tasks. Possible reasons for the apparent disparity between our own findings and earlier studies showing a hippocampal deficit are discussed in terms of both the potential differences in the demands placed on relational memory and of the proposed distinction between egocentric and allocentric visuospatial processing.
Deficits in recalling the past and imagining fictitious and future scenarios have been documented in patients with hippocampal damage and amnesia that was acquired in adulthood. By contrast patients with very early hippocampal damage and developmental amnesia are not impaired relative to control participants when imagining fictitious/future experiences. Recently, however, a patient (HC) with developmental amnesia, resulting from bilateral hippocampal atrophy, was reported to be impaired, thus raising a question about the true nature of event construction in the context of developmental amnesia. Here, we assessed HC on a test of imagination which explored her ability to construct fictitious events or personal plausible future events. Her scenario descriptions were analysed in detail along a range of parameters, using two different scoring methods. HCs performance was comparable to matched control participants on all measures relating to the imagination of fictitious and future scenarios. We then considered why she was reported as impaired in the previous study. We conclude that various features of the previous testing methodology may have contributed to the underestimation of HCs ability in that instance. Patients like HC with developmental amnesia may be successful at future-thinking tasks because their performance is not based on true visualisation or scene construction supported by the hippocampus, but rather on preserved world knowledge and semantic representations.
Virtually all information that enters the cortex must first pass through the thalamus. This prominent role has made the human thalamus a target for detailed imaging studies. It has previously been shown that probabilistic tractography together with cortical parcellation allowed subdivision of the thalamus into its constituent substructures. A new method is presented that allows the subdivision of the thalamus according to its cortical projection targets based on the assumption that any cortical region receives input from the thalamus and calculates the probability of connectivity distribution functions based on probabilistic tractography. The feasibility of the method was tested in a data set of 43 healthy children aged between 8 and 13 years. A thalamic parcellation pattern similar to that previously found in adults and children below the age of 2 years was obtained. However, no evidence for an age related change in cortical parcellation volumes were found in line with previously reported studies of thalamic volumes during development. Lower standard deviations were found for the two smallest projections, the sensory and occipital projection using the new method. Furthermore it was found, through comparison with a published thalamic atlas, that the method allowed the localization of the center of the different thalamic projection areas within an accuracy of 2 mm.
Compared to adults, relatively little is known about autobiographical memory and the ability to imagine fictitious and future scenarios in school-aged children, despite the importance of these functions for development and subsequent independent living. Even less is understood about the effect of early hippocampal damage on childrens memory and imagination abilities. To bridge this gap, we devised a novel naturalistic autobiographical memory task that enabled us to formally assess the memory for recent autobiographical experiences in healthy school-aged children. Contemporaneous with the autobiographical memories being formed, the children also imagined and described fictitious scenarios. Having established the performance of healthy school-aged children on these tasks, we proceeded to make comparisons with children (n=21) who had experienced neonatal hypoxia/ischaemia, and consequent bilateral hippocampal damage. Our results showed that healthy children could recall autobiographical events, including spatiotemporal information and specific episodic details. By contrast, children who had experienced neonatal hypoxia/ischaemia had impaired recall, with the specific details of episodes being lost. Despite this significant memory deficit they were able to construct fictitious scenarios. This is in clear contrast to adults with hippocampal damage, who typically have impaired autobiographical memory and deficits in the construction of fictitious and future scenarios. We speculate that the paediatric patients relatively intact semantic memory and/or some functionality in their residual hippocampi may underpin their scene construction ability.
Many studies report chronic deficits in visual processing in children born preterm. We investigated whether functional abnormalities in visual processing exist in children born preterm but without major neuromotor impairment (i.e. cerebral palsy). Twelve such children (< 33 weeks gestation or birthweight < 1000 g) without major neuromotor impairment and 12 born full-term controls were assessed at 8-12 years of age by means of ophthalmological assessment (visual acuity, colour vision, stereopsis, stereoacuity, visual fields, ocular motility, motor fusion), cognitive tests of visual-motor, visual-perceptual and visual-spatial skills and pattern-reversal visual evoked potentials (PR-VEPs). All participants also underwent magnetic resonance imaging (MRI) of the brain and neuromotor assessments. No significant differences were found between the groups on the ophthalmological, visual cognitive, neurological, neuromotor or MRI measures. The P100 component of the PR-VEP showed a significantly shorter latency in the preterm compared with the full-term participants. Whilst this P100 finding suggests that subtle abnormalities may exist at the neurophysiological level, we conclude that visual dysfunction is not systematically associated with preterm birth in the context of normal neurological status.
Patients with bilateral hippocampal damage acquired in adulthood who are amnesic for past events have also been reported to be impaired at imagining fictitious and future experiences. One such patient, P01, however, was found to be unimpaired on these tasks despite dense amnesia and 50% volume loss in both hippocampi. P01 might be an atypical case, and in order to investigate this we identified another patient with a similar neuropsychological profile. Jon is a well-characterised patient with developmental amnesia and 50% volume loss in his hippocampi. Interestingly both Jon and P01 retain some recognition memory ability, and show activation of residual hippocampal tissue during fMRI. Jons ability to construct fictitious and future scenarios was compared with the adult-acquired cases previously reported on this task and control participants. In contrast to the adult-acquired cases, but similar to P01, Jon was able to richly imagine both fictitious and future experiences in a comparable manner to control participants. Moreover, his constructions were spatially coherent. We speculate that the hippocampal activation during fMRI noted previously in P01 and Jon might indicate some residual hippocampal function which is sufficient to support their preserved ability to imagine fictitious and future scenarios.
Hemispherectomy (disconnection or removal of an entire cerebral hemisphere) is a rare surgical procedure used for the relief of drug-resistant epilepsy in children. After hemispherectomy, contralateral hemiplegia persists whereas gross expressive and receptive language functions can be remarkably spared. Motor speech deficits have rarely been examined systematically, thus limiting the accuracy of postoperative prognosis. We describe the speech profiles of hemispherectomized participants characterizing their intelligibility, articulation, phonological speech errors, dysarthric features, and execution and sequencing of orofacial speech and non-speech movements. Thirteen participants who had undergone hemispherectomy (six left, seven right; nine with congenital, four with acquired hemiplegia; operated between four months and 13 years) were investigated. Results showed that all participants were intelligible but showed a mild dysarthric profile characterized by neuromuscular asymmetry and reduced quality and coordination of movements, features that are characteristic of adult-onset unilateral upper motor neuron dysarthria, flaccid-ataxic variant. In addition, one left and four right hemispherectomy cases presented with impaired production of speech and non-speech sequences. No participant showed evidence of verbal or oral dyspraxia. It is concluded that mild dysarthria is persistent after left or right hemispherectomy, irrespective of age at onset of hemiplegia. These results indicate incomplete functional re-organization for the control of fine speech motor movements throughout childhood, and provide no evidence of hemispheric differences.
Seizures are common in children admitted with severe falciparum malaria and are associated with neuro-cognitive impairments. Prolonged febrile seizures are associated with hippocampal damage and impaired memory. It was hypothesized that severe malaria causes impaired everyday memory which may be associated with hippocampal damage.
A series of experiments test the recent claim that the hippocampus is necessary for the binding of features in working memory. Some potential limitations of studies underlying this claim are discussed, and an attempt is made to further test the hypothesis by studying a case of developmental amnesia whose extensively investigated pathology appears to be principally limited to the hippocampus, and who shows the expected deficit in episodic long-term memory. One series of experiments studied the short-term visual binding of color and shape under conditions ranging from simple presentation of colored objects through the more demanding task of combining the features when separated in space, or in time. A second set of experiments studied the capacity to use sentence structure to bind words into chunks in short-term verbal memory. Hippocampal pathology did not lead to a decrement on any of these tasks, suggesting that the hippocampus is not essential for short-term binding in working memory.
Developmental amnesia (DA) is a memory disorder due to hypoxia/ischaemia-induced damage to the hippocampus early in life. To test the hypothesis that this disorder is associated with a disproportionate impairment in recall vis-à-vis recognition, we examined a group of 10 patients with DA on the Doors and People test, which affords a quantitative comparison between measures of the two memory processes. The results supported the hypothesis in that the patients showed a sharp, though not complete, recall-recognition dissociation, exhibiting impairment on both measures relative to their matched controls, but with a far greater loss in recall than in recognition. Whether their relatively spared recognition ability is due to restriction of their medial temporal lobe damage to the hippocampus or whether it is due instead to their early age at injury is still uncertain.
The hippocampus, a structure located in the temporal lobes of the brain, is critical for the ability to recollect contextual details of past episodes. It is still debated whether the hippocampus also enables recognition memory for previously encountered context-free items. Brain imaging and neuropsychological patient studies have both individually provided conflicting answers to this question. We overcame the individual limitations of imaging and behavioral patient studies by combining them and observed a novel relationship between item memory and the hippocampus. We show that interindividual variability of hippocampal volumes in a large patient population with graded levels of hippocampal volume loss and controls correlates with context, but not item-memory performance. Nevertheless, concurrent measures of brain activity using magnetoencephalography reveal an early (350 ms) but sustained hippocampus-dependent signal that evolves from an item signal into a context memory signal. This is temporally distinct from an item-memory signal that is not hippocampus dependent. Thus, we provide evidence for a hippocampus-dependent item-memory process that initiates context retrieval without making a substantial contribution to item recognition performance. Our results reconcile contradictory evidence concerning hippocampal involvement in item memory and show that hippocampus-dependent mnemonic processes are more rapid than previously believed.
The early diagnosis of Rasmussens syndrome (RS) is often difficult, with differentiation between RS and focal cortical dysplasia (FCD) at epilepsy onset problematic. This study reviewed electroencephalography (EEG) in the two conditions for early indicators of either pathology.
Monkeys can easily form lasting central representations of visual and tactile stimuli, yet they seem unable to do the same with sounds. Humans, by contrast, are highly proficient in auditory long-term memory (LTM). These mnemonic differences within and between species raise the question of whether the human ability is supported in some way by speech and language, e.g., through subvocal reproduction of speech sounds and by covert verbal labeling of environmental stimuli. If so, the explanation could be that storing rapidly fluctuating acoustic signals requires assistance from the motor system, which is uniquely organized to chain-link rapid sequences. To test this hypothesis, we compared the ability of normal participants to recognize lists of stimuli that can be easily reproduced, labeled, or both (pseudowords, nonverbal sounds, and words, respectively) versus their ability to recognize a list of stimuli that can be reproduced or labeled only with great difficulty (reversed words, i.e., words played backward). Recognition scores after 5-min delays filled with articulatory-suppression tasks were relatively high (75-80% correct) for all sound types except reversed words; the latter yielded scores that were not far above chance (58% correct), even though these stimuli were discriminated nearly perfectly when presented as reversed-word pairs at short intrapair intervals. The combined results provide preliminary support for the hypothesis that participation of the oromotor system may be essential for laying down the memory of speech sounds and, indeed, that speech and auditory memory may be so critically dependent on each other that they had to coevolve.
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