Generalized versus selective cognitive impairments resulting from brain damage sustained in childhood.
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Aphasia↗
Biomedical subjects
F Vargha-Khadem
Publications and source records attributed to F Vargha-Khadem.
The effects of bilateral hippocampal damage on fMRI regional activations and interactions during memory retrieval.
Using functional magnetic resonance imaging (fMRI) we examined successful retrieval of real-world memories in a patient (Jon) with selective bilateral hippocampal pathology resulting from perinatal hypoxia compared with healthy control subjects. Jon activated the same brain regions during memory retrieval as control subjects, both medial and lateral on the left. In contrast to controls, Jon also activated many homologous regions on the right. In spite of having 50% volume loss bilaterally in his hippocampi, retrieval in Jon was associated with increased activation of the hippocampi. Furthermore, hippocampal activity, as with the controls, was differential, being most responsive to retrieval of autobiographical events compared with other memory types (autobiographical facts, public events, general knowledge). Jon made a distinction between events that the control subjects did not make, namely that some of the autobiographical and public events he clearly remembered, while others he found that he knew about but did not truly remember. His hippocampi and medial frontal cortex were significantly more active during retrieval of events for which he had clear and conscious recollection compared with those he knew as much about, including the context, but could not remember experiencing. Although Jon activates the same network of brain regions as the controls (albeit bilaterally), and with the same pattern of response in the hippocampus, the communication between regions differs from controls with regard to hippocampal-cortical connectivity. In controls there was increased effective connectivity between parahippocampal cortex and hippocampus, specifically during the retrieval of autobiographical events. In contrast, this increase was not apparent in Jon; rather, retrieval of autobiographical events elicited greater interaction between the hippocampus and retrosplenial cortex, and also increased interaction between retrosplenial and medial frontal cortex. This study underlines the value of scanning patients using fMRI while they undertake tasks they can perform, in this case allowing us to confirm the functionality of remaining tissue in the damaged hippocampi, and to appreciate the neural basis of a distinction (remember/know) that control subjects do not make. Besides refining our knowledge of the hippocampal role in autobiographical event memory, this study indicates that recruitment of bilateral regions during memory retrieval, and altered patterns of effective connectivity between brain regions may be important indicators of disordered memory.
Adult↗
Oral dyspraxia in inherited speech and language impairment and acquired dysphasia.
Half of the members of the KE family suffer from an inherited verbal dyspraxia. The affected members of the family have a lasting impairment in phonology and syntax. They were given various tests of oral praxis to investigate whether their deficit extends to nonverbal movements. Performance was compared to adult patients with acquired nonfluent dysphasia, those with comparable right-hemisphere lesions, and age-matched controls. Affected family members and patients with nonfluent dysphasia were impaired overall at performing oral movements, particularly combinations of movements. It is concluded that affected members of the KE family resemble patients with acquired dysphasia in having difficulties with oral praxis and that speech and language problems of affected family members arise from a lower level disorder.
Adolescent↗
Pitch and timing abilities in inherited speech and language impairment.
Members of the KE family who suffer from an inherited developmental speech-and-language disorder and normal, age-matched, controls were tested on musical abilities, including perception and production of pitch and rhythm. Affected family members were not deficient in either the perception or production of pitch, whether this involved either single notes or familiar melodies. However, they were deficient in both the perception and production of rhythm in both vocal and manual modalities. It is concluded that intonation abilities are not impaired in the affected family members, whereas their timing abilities are impaired. Neither their linguistic nor oral praxic deficits can be at the root of their impairment in timing; rather, the reverse may be true.
Adolescent↗
The SPCH1 region on human 7q31: genomic characterization of the critical interval and localization of translocations associated with speech and language disorder.
The KE family is a large three-generation pedigree in which half the members are affected with a severe speech and language disorder that is transmitted as an autosomal dominant monogenic trait. In previously published work, we localized the gene responsible (SPCH1) to a 5.6-cM region of 7q31 between D7S2459 and D7S643. In the present study, we have employed bioinformatic analyses to assemble a detailed BAC-/PAC-based sequence map of this interval, containing 152 sequence tagged sites (STSs), 20 known genes, and >7.75 Mb of completed genomic sequence. We screened the affected chromosome 7 from the KE family with 120 of these STSs (average spacing <100 kb), but we did not detect any evidence of a microdeletion. Novel polymorphic markers were generated from the sequence and were used to further localize critical recombination breakpoints in the KE family. This allowed refinement of the SPCH1 interval to a region between new markers 013A and 330B, containing approximately 6.1 Mb of completed sequence. In addition, we have studied two unrelated patients with a similar speech and language disorder, who have de novo translocations involving 7q31. Fluorescence in situ hybridization analyses with BACs/PACs from the sequence map localized the t(5;7)(q22;q31.2) breakpoint in the first patient (CS) to a single clone within the newly refined SPCH1 interval. This clone contains the CAGH44 gene, which encodes a brain-expressed protein containing a large polyglutamine stretch. However, we found that the t(2;7)(p23;q31.3) breakpoint in the second patient (BRD) resides within a BAC clone mapping >3.7 Mb distal to this, outside the current SPCH1 critical interval. Finally, we investigated the CAGH44 gene in affected individuals of the KE family, but we found no mutations in the currently known coding sequence. These studies represent further steps toward the isolation of the first gene to be implicated in the development of speech and language.
Base Sequence↗
The reorganization of sensorimotor function in children after hemispherectomy. A functional MRI and somatosensory evoked potential study.
Children who have suffered extensive unilateral brain injury early in life may show a remarkable degree of residual sensorimotor function. It is generally believed that this reflects the high capacity of the immature brain for cerebral reorganization. In this study, we investigated 17 patients who had undergone hemispherectomy for relief from seizures; eight of the patients had congenital brain damage and nine had sustained their initial insult at the age of 1 year or older. Sensorimotor functions of the hand were investigated using functional MRI (fMRI) during a passive movement task, somatosensory evoked potentials (SEPs) arising from electrical and vibration stimulation, and behavioural tests including grip strength, double simultaneous stimulation and joint position sense. On fMRI, two of the eight patients studied with this technique (one with congenital damage and one with damage acquired at the age of 3 years) showed activation in the sensorimotor cortex of the remaining hemisphere with passive movement of the hemiplegic hand. The location of the ipsilateral brain activation was similar to that found on movement of the normal contralateral hand, although the latter was greater in spatial extent. In one of these patients, a greater role was demonstrated for the ipsilateral secondary sensorimotor area (compared with the ipsilateral primary sensorimotor area) for movement of the hemiplegic hand than for movement of the normal hand. Median nerve stimulation of the hemiplegic hand showed reproducible early-latency ipsilateral SEP components in the remaining sensorimotor cortex in 10 of the 17 patients (five with congenital and five with acquired disease). Five of the patients who demonstrated ipsilateral electrical SEPs also showed ipsilateral vibration SEPs (two with congenital and three with acquired disease). The behavioural tests revealed residual sensorimotor function in 14 of the patients; however, not all of the patients who exhibited ipsilateral SEP or fMRI responses had residual sensorimotor function in the hemiplegic hand. Ipsilateral sensorimotor responses were demonstrated both in patients with congenital disease and those with acquired disease, suggesting that factors additional to aetiology and age at injury may influence the degree of residual sensorimotor function and cerebral reorganization.
Adolescent↗
Developmental amnesia associated with early hypoxic-ischaemic injury.
We recently reported on three young patients with severe impairments of episodic memory resulting from brain injury sustained early in life. These findings have led us to hypothesize that such impairments might be a previously unrecognized consequence of perinatal hypoxic-ischaemic injury. Neuropsychological and quantitative magnetic resonance investigations were carried out on five young patients, all of whom had suffered hypoxic-ischaemic episodes at or shortly after birth. All five patients showed severe impairments of episodic memory (memory for events), with relative preservation of semantic memory (memory for facts). However, none had any of the major neurological deficits that are typically associated with hypoxic-ischaemic injury, and all attended mainstream schools. Quantitative magnetic resonance investigations revealed severe bilateral hippocampal atrophy in all cases. As a group, the patients also showed bilateral reductions in grey matter in the regions of the putamen and the ventral part of the thalamus. On the basis of their clinical histories and the pattern of magnetic resonance findings, we attribute the patients' pathology and associated memory impairments primarily to hypoxic-ischaemic episodes sustained very early in life. We suggest that the degree of hypoxia-ischaemia was sufficient to produce selective damage to particularly vulnerable regions of the brain, notably the hippocampi, but was not sufficient to result in the more severe neurological and cognitive deficits that can follow hypoxic-ischaemic injury. The impairments in episodic memory may be difficult to recognize, particularly in early childhood, but this developmental amnesia can have debilitating consequences, both at home and at school, and may preclude independent life in adulthood.
Adolescent↗
Hippocampal volume and everyday memory in children of very low birth weight.
Children born preterm and of very low birth weight have an increased incidence of learning difficulties, but little is known about the specific nature of their cognitive deficits and the underlying neuropathology. We hypothesized that their vulnerability to hypoxic, metabolic, and nutritional insults would lead to reduced hippocampal volumes and to deficits in memory because of the role of the hippocampus in this domain of cognition. Neuropsychological and magnetic resonance imaging methods were used to investigate this hypothesis in adolescents born preterm (< or = 30 wk gestation, n = 11) or full-term (n = 8). The preterm group had significantly smaller hippocampal volumes bilaterally, despite equivalent head size, and showed specific deficits in certain aspects of everyday memory, both on objective testing and as indicated by parental questionnaires. The preterm group also had a specific deficit in numeracy. The reduced hippocampal volumes and deficits in everyday memory have previously been unrecognized, but their prevalence in a group of neurologically normal children is striking.
Adolescent↗
Detecting bilateral abnormalities with voxel-based morphometry.
In this article we describe a new method, using SPM99, that searches explicitly for bilateral structural abnormalities. Children with bilateral pathology have a poorer prognosis than children with unilateral damage. After brain injury or disease in childhood, it is thought that rescue of function is only possible if the neuronal substrates of that function are preserved and operational in at least one hemisphere [Vargha-Khadem and Mishkin, 1997]. If this is the case, the detection of bilateral abnormalities would greatly facilitate more accurate prognosis in children with brain injury or developmental disorders. We have therefore developed a technique to detect bilateral abnormalities that uses conjunction analysis with voxel based morphometry. It is illustrated using a group of patients with bilateral hypoxic-ischaemic damage to the hippocampus. The approach is shown to have enhanced specificity and sensitivity relative to conventional unilateral characterisations.
Amnesia↗
Functional and structural brain abnormalities associated with a genetic disorder of speech and language.
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Brain↗
Early brain pathology and its relation to cognitive impairment: the role of quantitative magnetic resonance techniques.
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Aging↗
Neural basis of an inherited speech and language disorder.
Investigation of the three-generation KE family, half of whose members are affected by a pronounced verbal dyspraxia, has led to identification of their core deficit as one involving sequential articulation and orofacial praxis. A positron emission tomography activation study revealed functional abnormalities in both cortical and subcortical motor-related areas of the frontal lobe, while quantitative analyses of magnetic resonance imaging scans revealed structural abnormalities in several of these same areas, particularly the caudate nucleus, which was found to be abnormally small bilaterally. A recent linkage study [Fisher, S., Vargha-Khadem, F., Watkins, K. E., Monaco, A. P. & Pembry, M. E. (1998) Nat. Genet. 18, 168-170] localized the abnormal gene (SPCH1) to a 5. 6-centiMorgan interval in the chromosomal band 7q31. The genetic mutation or deletion in this region has resulted in the abnormal development of several brain areas that appear to be critical for both orofacial movements and sequential articulation, leading to marked disruption of speech and expressive language.
Brain↗
Amnesia and the organization of the hippocampal system.
Early hippocampal injury in humans has been found to result in a limited form of global anterograde amnesia. At issue is whether the limitation is qualitative, with the amnesia reflecting substantially greater impairment in episodic than in semantic memory, or only quantitative, with both episodic and semantic memory being partially and equivalently impaired. Evidence from neuroanatomical and lesion studies in animals suggests that the hippocampus and subhippocampal cortices form a hierarchically organized system, such that the greatest convergence of information (and, by implication, the richest amount of association) takes place within the hippocampus, located at the top of the hierarchy. On the one hand, this evidence is consistent with the view that selective hippocampal damage produces a differential impairment in context-rich episodic memory as compared with context-free semantic memory, because only the latter can be supported by the subhippocampal cortices. On the other hand, given the system's hierarchical form of organization, this dissociation of deficits is difficult to prove, because a quantitatively limited deficit will nearly always be a viable alternative. A final choice between the alternative views is therefore likely to depend less on further evidence gathered in brain-injured patients than on which view accounts for more of the data gathered from converging approaches to the problem.
Amnesia↗
Localisation of a gene implicated in a severe speech and language disorder.
Between 2 and 5% of children who are otherwise unimpaired have significant difficulties in acquiring expressive and/or receptive language, despite adequate intelligence and opportunity. While twin studies indicate a significant role for genetic factors in developmental disorders of speech and language, the majority of families segregating such disorders show complex patterns of inheritance, and are thus not amenable for conventional linkage analysis. A rare exception is the KE family, a large three-generation pedigree in which approximately half of the members are affected with a severe speech and language disorder which appears to be transmitted as an autosomal dominant monogenic trait. This family has been widely publicised as suffering primarily from a defect in the use of grammatical suffixation rules, thus supposedly supporting the existence of genes specific to grammar. The phenotype, however, is broader in nature, with virtually every aspect of grammar and of language affected. In addition, affected members have a severe orofacial dyspraxia, and their speech is largely incomprehensible to the naive listener. We initiated a genome-wide search for linkage in the KE family and have identified a region on chromosome 7 which co-segregates with the speech and language disorder (maximum lod score = 6.62 at theta = 0.0), confirming autosomal dominant inheritance with full penetrance. Further analysis of microsatellites from within the region enabled us to fine map the locus responsible (designated SPCH1) to a 5.6-cM interval in 7q31, thus providing an important step towards its identification. Isolation of SPCH1 may offer the first insight into the molecular genetics of the developmental process that culminates in speech and language.
Chromosome Mapping↗
Cognitive deficits associated with frontal-lobe infarction in children with sickle cell disease.
This study examined the cognitive manifestations of frontal-lobe infarction in a population of children with sickle cell disease (SCD). Forty-one patients with SCD underwent MRI. Five patients with stroke symptoms had large infarcts encroaching on the tissue of the frontal lobes. Four patients without symptoms had smaller frontal-lobe infarcts. The patients with stroke were significantly impaired on measures of intelligence, memory, and frontal-lobe function (Wisconsin Card Sorting Test, WCST) compared with both the patients with normal MRI scans (N=30) and a group of sibling controls (N=15), who did not differ from each other. Patients with covert infarction obtained scores on the intelligence tests and the WCST that fell in between those of the stroke patients and the other two groups. This trend toward impairment suggests that patients with covert infarction are at similar risk for cognitive deficits to those with stroke.
Adolescent↗
Hierarchical organization of cognitive memory.
This paper addresses the question of the organization of memory processes within the medial temporal lobe. Evidence obtained in patients with late-onset amnesia resulting from medial temporal pathology has given rise to two opposing interpretations of the effects of such damage on long-term cognitive memory. One view is that cognitive memory, including memory for both facts and events, is served in a unitary manner by the hippocampus and its surrounding cortices; the other is that the basic function affected in amnesia is event memory, the memory for factual material often showing substantial preservation. Recent findings in patients with amnesia resulting from relatively selective hippocampal damage sustained early in life suggest a possible reconciliation of the two views. The new findings suggest that the hippocampus may be especially important for event as opposed to fact memory, with the surrounding cortical areas contributing to both. Evidence from neuroanatomical and neurobehavioural studies in monkeys is presented in support of this proposal.
Amnesia↗
Differential effects of early hippocampal pathology on episodic and semantic memory.
Global anterograde amnesia is described in three patients with brain injuries that occurred in one case at birth, in another by age 4, and in the third at age 9. Magnetic resonance techniques revealed bilateral hippocampal pathology in all three cases. Remarkably, despite their pronounced amnesia for the episodes of everyday life, all three patients attended mainstream schools and attained levels of speech and language competence, literacy, and factual knowledge that are within the low average to average range. The findings provide support for the view that the episodic and semantic components of cognitive memory are partly dissociable, with only the episodic component being fully dependent on the hippocampus.
Adolescent↗
A longitudinal study of early intellectual development in hemiplegic children.
Thirty-eight 3- to 5-year-old children with unilateral lesions sustained pre- or peri-natally were studied longitudinally over a 2-year period, and their IQ scores compared with those of 20 "medical' controls. The failure to discover laterality effects following early unilateral injury supports the hypothesis of at least broad functional equipotentiality. There were few decrements in intellectual functioning provided the injury was not accompanied by seizures. The presence of seizures in contrast had a deleterious effect on both verbal and nonverbal aspects of cognitive functioning. While the IQs of the hemiplegic groups showed considerable stability over the 2-year span of the study, there was evidence that performance IQ, even in seizure-free patients, might be selectively impaired because of competition within the intact neural space for the sparing of verbal IQ.
Analysis of Variance↗