Dexras1 a unique ras-GTPase interacts with NMDA receptor activity and provides a novel dissociation between anxiety, working memory and sensory gating.

Dexras1 is a novel GTPase that acts at a confluence of signaling mechanisms associated with psychiatric and neurological disease including NMDA receptors, NOS1AP and nNOS. Recent work has shown that Dexras1 mediates iron trafficking and NMDA-dependent neurodegeneration but a role for Dexras1 in normal brain function or psychiatric disease has not been studied. To test for such a role, mice with germline knockout (KO) of Dexras1 were assayed for behavioral abnormalities as well as changes in NMDA receptor subunit protein expression. Because Dexras1 is up-regulated during stress or by dexamethasone treatment, we included measures associated with emotion including anxiety and depression. Baseline anxiety-like measures (open field and zero maze) were not altered, nor were depression-like behavior (tail suspension). Measures of memory function yielded mixed results, with no changes in episodic memory (novel object recognition) but a significant decrement on working memory (T-maze). Alternatively, there was an increase in pre-pulse inhibition (PPI), without concomitant changes in either startle amplitude or locomotor activity. PPI data are consistent with the direction of change seen following exposure to dopamine D2 antagonists. An examination of NMDA subunit expression levels revealed an increased expression of the NR2A subunit, contrary to previous studies demonstrating down-regulation of the receptor following antipsychotic exposure (Schmitt et al., 2003) and up-regulation after exposure to isolation rearing (Turnock-Jones et al., 2009). These findings suggest a potential role for Dexras1 in modulating a selective subset of psychiatric symptoms, possibly via its interaction with NMDARs and/or other disease-related binding-partners. Furthermore, data suggest that modulating Dexras1 activity has contrasting effects on emotional, sensory and cognitive domains.

VMAT1 deletion causes neuronal loss in the hippocampus and neurocognitive deficits in spatial discrimination.

Vesicular monoamine transporters (VMAT) are involved in presynaptic storage and release of neurotransmitters. While it was thought initially that only VMAT2 is brain expressed and VMAT1 is present only in the periphery, recent data have challenged the exclusive expression of VMAT2 in the brain. To further elucidate the role of VMAT1 brain expression and its potential role in neuropsychiatric disorders, we have investigated mice lacking VMAT1. Comparison of wildtype and knock-out (KO) mice using qPCR and immunohistochemistry documents the expression of VMAT1 in the brain. Deletion of VMAT1 leads to increased hippocampal apoptosis and reduced neurogenesis as assessed by caspase-3-labeling and 5-bromo-deoxy-uridine-labeling. Behavioral data show that mice lacking VMAT1 have neurocognitive deficits. VMAT2 expression is not altered in VMAT1 KO mice, suggesting a distinct role of VMAT1. Our data support VMAT1 brain expression and suggest that VMAT1 plays a key role in survival of hippocampal neurons and thus might contribute to neurocognitive deficits observed in neuropsychiatric disorders.

Strain differences in the effects of chronic corticosterone exposure in the hippocampus.

Stress hormones are thought to be involved in the etiology of depression, in part, because animal models show they cause morphological damage to the brain, an effect that can be reversed by chronic antidepressant treatment. The current study examined two mouse strains selected for naturalistic variation of tissue regeneration after injury for resistance to the effects of chronic corticosterone (CORT) exposure on cell proliferation and neurotrophin mobilization. The wound healer MRL/MpJ and control C57BL/6J mice were implanted subcutaneously with pellets that released CORT for 7 days. MRL/MpJ mice were resistant to reductions of hippocampal cell proliferation by chronic exposure to CORT when compared to vulnerable C57BL/6J mice. Chronic CORT exposure also reduced protein levels of brain-derived neurotrophic factor (BDNF) in the hippocampus of C57BL/6J but not MRL/MpJ mice. CORT pellet exposure increased circulating levels of CORT in the plasma of both strains in a dose-dependent manner although MRL/MpJ mice may have larger changes from baseline. The strains did not differ in circulating levels of corticosterone binding globulin (CBG). There were also no strain differences in CORT levels in the hippocampus, nor did CORT exposure alter glucocorticoid receptor or mineralocorticoid receptor expression in a strain-dependent manner. Strain differences were found in the N-methyl-D-aspartate (NMDA) receptor, and BDNF I and IV promoters. Strain and CORT exposure interacted to alter tropomyosine-receptor-kinase B (TrkB) expression and this may be a potential mechanism protecting MRL/MpJ mice. In addition, differences in the inflammatory response of matrix metalloproteinases (MMPs) may also contribute to these strain differences in resistance to the deleterious effects of CORT to the brain.

Clinical presentations and molecular basis of complement C1r deficiency in a male African-American patient with systemic lupus erythematosus.

Homozygous deficiencies of early components for complement activation are among the strongest genetic risk factors for human systemic lupus erythematosus (SLE). Eleven cases of C1r deficiency are documented but this is the first report on the molecular basis of C1r deficiency. The proband is an African-American male who developed SLE at 3 months of age. He had a discoid lupus rash and diffuse proliferative glomerulonephritis. Serum complement analysis of the patient showed zero CH50 activity, undetectable C1r, and reduced levels of C1s, but highly elevated levels of complement C4, C2, and C1-inhibitor. The coding regions of the mutant C1R gene with 11 exons located at chromosome 12p13 were polymerase chain reaction (PCR)-amplified and sequenced to completion. DNA sequencing revealed a homozygous C→T mutation at nucleotide-6392 in exon 10 of the C1R gene, resulting in a nonsense mutation from Arg-380 (R380X). The patient's clinically normal mother was heterozygous for this mutation. A sequence-specific primer (SSP) PCR coupled with StuI-restriction fragment length polymorphism (RFLP) was developed to detect the novel mutation. Screening of 209 African-American SLE patients suggested that the R380X mutation is a rare causal variant. Mutations leading to early complement component deficiencies in SLE are mostly private variants with large effects.

Cognitive and linguistic correlates of children's discourse after closed head injury: a three-year follow-up.

The discourse of 91 children who had sustained severe (n = 68) or mild (n = 23) closed head injury (CHI) was examined at least three years postinjury. The groups' retellings of a narrative story were analyzed according to two domains, information and language. In comparison to the mild CHI group, the severe group produced stories characterized by reduced content and information, impaired organization, fewer words, and less complex sentences. The relationships between discourse production and the groups' performance on measures of language, executive function, memory, and processing speed were examined. Correlations were found between discourse production and general verbal ability including verbal fluency. Correlations were also found for discourse performance and executive function measures associated with problem solving and working memory. Site and extent of lesion were not useful in predicting discourse production. These findings indicate that children who sustain a severe closed head injury during early to middle childhood are at risk for persisting deficits in discourse processing and other cognitive abilities.

Memory functions in children with early hydrocephalus.

Children with arrested, shunted, and no hydrocephalus were compared on verbal and nonverbal memory tasks assessing multiple components of memory. A gradient of severity was hypothesized, with the shunted hydrocephalus group expected to exhibit the most significant memory impairments and the arrested group expected to perform more poorly than children with no hydrocephalus. Etiologies of prematurity, spina bifida, and aqueductal stenosis were represented by 157 participants. Results supported the hypothesis; the shunted hydrocephalus group performed poorer on all memory measures. Differences for the arrested group were less frequently statistically significant relative to children with no hydrocephalus. Irrespective of etiology, the shunted hydrocephalus group exhibited a pattern of performance suggestive of encoding and retrieval deficits on both verbal and nonverbal tasks, showing a pervasive disturbance of memory processes.

Children's narratives following traumatic brain injury: linguistic structure, cohesion, and thematic recall.

Narrative discourse and intellectual functioning were examined 3 years following traumatic brain injury (TBI) in children 1 to 8 years of age at the time of injury. The language-impaired TBI group (n = 9) had language deficits during the subacute stage of recovery; their performance was contrasted with that of a TBI comparison group equated on neurologic and demographic variables that did not show subacute language impairment (n = 8) and a sibling comparison group (n = 9). The language-impaired TBI group had lower Verbal and Full-Scale IQ scores and produced fewer words and utterances than the sibling group on a story retelling task; their stories were characterized by fewer complete referential and lexical ties and more referential errors, indicating difficulty conjoining meaning across sentences. The language-impaired TBI group recalled approximately one-third of the propositions needed to maintain the story theme and made more errors sequencing the propositions than either the TBI or the sibling comparison groups. Group differences were not obtained on the Performance IQ scores or on measures of rate or fluency of speech production, mazes, use of conjunctives, or naming errors. The discourse deficiencies of children with TBI and acute language impairment were most pronounced at the level of cognitive organization of the text reflecting text macrostructure and were least apparent at the level of lexical and sentential organization reflecting text microstructure. Results are discussed in terms of the vulnerability of developing language abilities to disruption by brain injury.

Quality of life perception in patients with intractable epilepsy or pseudoseizures.

OBJECTIVES: To contrast and compare self-reported quality of life in patients with intractable epilepsy and pseudoseizures and to examine the relationship between self-reports and objective measures of cognitive functioning in both of these groups. DESIGN: Case series using profile analysis and analysis of covariance. SETTING: University epilepsy surgery program. PARTICIPANTS: Forty-three patients with intractable complex partial seizures of unilateral temporal lobe origin and 25 patients with pseudoseizures. MEASURES: Quality of Life in Epilepsy Inventory-89; neuropsychological tests assessing verbal memory, nonverbal memory, naming, and attention; and the Depression Scale (2) of the MMPI-2 (Minnesota Multiphasic Personality Inventory). RESULTS: Patients with pseudoseizures described themselves as more limited in the physical health domain than patients with complex partial seizures. Self-perceptions of cognitive functioning were similar between groups, despite the superior performance of patients with pseudoseizures on objective measures. Self-perception of cognitive dysfunction was related to mood disorder in the pseudoseizure group only, and there were no relationships between subjective and objective measurements of cognitive status within this group independent of mood disorder. For the complex partial seizures group, relationships between subjective and objective measures of cognitive function were dependent on the side of seizure onset. CONCLUSIONS: Results are consistent with hypotheses that suggest that patients with pseudoseizures focus on physical rather than psychological explanations for stress, and that this focus is related, at least in a subgroup of patients, to mood disorder. Results also provide support for the validity of the Quality of Life in Epilepsy Inventory-89 in populations with intractable seizure disorder, although there is evidence for a possible floor effect on some of the subscales.

Effects of intraventricular hemorrhage and hydrocephalus on the long-term neurobehavioral development of preterm very-low-birthweight infants.

Measures of intelligence, neuropsychological functions, academic skills, and behavioral adjustment were obtained at school-age from children born preterm with no hydrocephalus (N=29), arrested hydrocephalus (N=19), and shunted hydrocephalus (N=17), and a term comparison group (N=23). Most children also received concurrent neurological examinations and MRI brain scans. Results revealed significantly poorer neurobehavioral development in all four domains in preterm children with shunted hydrocephalus. Despite abnormal MRI findings in virtually all children with arrested hydrocephalus, significant differences between preterm children with arrested hydrocephalus and those with no hydrocephalus were largely in areas involving attentional and academic skills. Preterm children with no hydrocephalus tended to show poorer motor development relative to term children. Neurological abnormalities were restricted to children with spasticity in the arrested (N=2) and shunted (N=10) groups. These results highlight the importance of separating cases according to residual neurological and neuroimaging abnormalities in accounting for variations in the neurobehavioral development of preterm, low-birth-weight infants.

Identification of side of seizure onset in temporal lobe epilepsy using memory tests in the context of reading deficits.

Sixty patients with temporal lobe epilepsy were classified into reading deficient (RD; n = 21) and non-reading deficient (non-RD; n = 39) groups. Selective deficits in verbal or nonverbal memory, consistent with side of seizure onset, were evident in the non-RD patients. Both verbal and nonverbal memory performance were reduced equivalently in individuals with RD, regardless of side of seizure onset. As a result, memory tests that were accurate in identifying side of seizure onset in the non-RD group were not as accurate in the RD group. When individual cases were classified using a clinically applicable decision rule, significantly more RD patients were either unclassifiable or incorrectly classified than were non-RD patients. Findings suggest that preoperative memory data obtained from individuals with epilepsy and evidence of RD may not be as valid an indicator of side of seizure onset as are those obtained from patients without RD.

On the surgical treatment of refractory epilepsy in tuberous sclerosis complex.

The role of surgery in the treatment of refractory epilepsy (RE) in tuberous sclerosis complex (TSC) is poorly defined. Four patients with RE and TSC were evaluated for epilepsy surgery from 1994 to 1996. Three of four patients developed infantile spasms within 5 months of birth. These progressed to frequent complex partial and generalized tonic/myoclonic seizures refractory to antiepileptic drug therapy. Neuroimaging revealed typical findings of TSC including calcified lesions consistent with hamartomas. Clinical and EEG evidence suggested an epileptic focus near a prominent lesion in each child. This was confirmed using magnetic source imaging in 1 case. All patients underwent inpatient continuous video-EEG monitoring followed by temporal lobectomy or focal cortical resection with intraoperative EEG. Age at operation ranged from 5 to 13 years. Three out of 4 patients experienced a greater than 90% decrease in seizure activity. One patient continues to have rare complex partial seizures, and 1 has rare simple partial seizures. Tumor DNA analysis revealed mutations in the TSC1 gene in case 1 and the TSC2 gene in case 2; no mutations have been identified yet in cases 3 and 4. Temporal lobectomy and focal cortical resection can result in improved seizure control in patients with TSC and RE.

Corpus callosotomy for medically intractable seizures.

To identify factors influencing outcome and morbidity in patients selected for corpus callosotomy, we retrospectively reviewed 23 patients with intractable generalized seizures who underwent corpus callosotomy between 1991 and 1994. Three patients had a complete corpus callosotomy, while 20 had an anterior callosotomy. Three of those patients subsequently had completion of the anterior callosotomy. Overall, 41% of patients were nearly or completely free of the seizure types targeted for surgical treatment, while another 45% had seizures less than half as frequently. Four patients developed simple partial motor seizures after callosotomy. A transient disconnection syndrome was observed in 57% of patients. The best predictor of good outcome was a normal preoperative MRI. Mentally retarded patients had poorer outcomes. Outcome was not predicted by extent of callosal section or lateralization on neurological examination, EEG, MRI, and SPECT. Completion of anterior callosotomy resulted in significant reductions in seizure frequency. Though most patients do not become seizure-free after corpus callosotomy, worthwhile palliation of an otherwise intractable illness can be achieved. An analysis of prognostic factors should lead to better selection of patients for surgery.

Asymmetries in the effect of side of seizure onset on recognition memory following intracarotid amobarbital injection.

PURPOSE: To assess interhemispheric differences in recognition memory for objects during the intracarotid amobarbital sodium procedure (IAP). METHODS: The recognition memory for real objects of patients with either right (RTLE; n = 28) or left (LTLE; n = 22) temporal lobe epilepsy was assessed at baseline, and after left and right intracarotid amobarbital sodium injection. RESULTS: There were no differences between groups on baseline performance. Performance following injection ipsilateral to the side of seizure focus was relatively lower for the LTLE as compared with the RTLE group, but this difference did not reach statistical significance. However, performance following injection contralateral to the side of seizure focus was significantly lower for the RTLE as compared with the LTLE group. Within-group differences in performance after ipsilateral as compared with contralateral injection were significant for the RTLE but not the LTLE group. The difference in interhemispheric asymmetry in IAP memory performance between RTLE and LTLE groups was reflected in decreased ability to classify LTLE patients as compared with RTLE patients about side of seizure onset, using a clinically applicable decision rule. CONCLUSIONS: Recognition memory during the IAP for real objects, simultaneously named and presented visually during encoding, is mediated effectively by both the left and right hemisphere when there is no seizure focus present. However, memory appears to be more vulnerable to the presence of a seizure focus in the right as compared with the left hemisphere.

Effects of temporal lobe epilepsy on spatial and figural aspects of memory for a complex geometric figure.

The preoperative delayed memory performance on the Rey-Osterrieth Complex Figure (Lezak, 1983) of 54 patients with complex partial seizures of temporal lobe origin was analyzed using 3 different indices. One index (composite) was derived using a common scoring method that included both spatial and figural aspects of memory in its score. The other two indices were derived emphasizing either spatial or figural aspects of memory for the elements of the figure separately. All 3 indices distinguished between individuals with right-sided (RTLE) and left-sided (LTLE) seizure onset. However, spatial memory was significantly lower than figural memory in individuals with RTLE as compared to those with LTLE. Both the spatial and figural memory indices were significantly lower in the presence of magnetic resonance imaging (MRI) evidence for hippocampal sclerosis in individuals with RTLE. Results suggest that while both the spatial and figural aspects of nonverbal memory are sensitive to right hippocampal dysfunction, figural memory may be less vulnerable to the effects of RTLE.

Lateralization of memory for music: evidence from the intracarotid sodium amobarbital procedure.

The present study was conducted to determine whether material-specific memory for unfamiliar tonal patterns could be demonstrated for the right temporal lobe during the intracarotid sodium amytal procedure (IAP). Thirty-one patients with intractable complex partial seizures associated with either left temporal lobe epilepsy (LTLE) or right temporal lobe epilepsy (RTLE) underwent assessment of memory for tonal patterns during a baseline phase and right and left cerebral hemisphere anaesthesia during the IAP. Patients were presented unfamiliar tonal patterns which were later selected from a set of distracter patterns. Findings indicated that there was no difference between the LTLE and RTLE patients during injection of the right cerebral hemisphere suggesting no specific involvement of left mesial temporal structures. However, a significant effect was noted during left injection with the LTLE group performing significantly better than the RTLE group. This latter finding supports a specific role of right mesial temporal lobe structures in mediating memory for music.

Regional brain tissue composition in children with hydrocephalus. Relationships with cognitive development.

OBJECTIVE: To determine whether children with shunted hydrocephalus show variations in regional brain tissue composition that relate to cognitive functions. DESIGN: Nonequivalent control group. PATIENTS AND METHODS: Magnetic resonance imaging (MRI) and cognitive skills assessments were obtained on 28 children, 6 to 9 years of age, with shunted hydrocephalus and 13 normal control subjects comparable in age, gender, ethnicity, and socioeconomic status. Three consecutive MRI slices below the vertex were segmented using a fuzzy clustering algorithm to separate pixels into gray matter, white matter, and cerebrospinal fluid (CSF) in quadrants representing left and right anterior and posterior brain regions. The cognitive skills assessments included the Wechsler Intelligence Scale for Children-Revised verbal and performance IQ scores, neuropsychological composites of language and visuospatial skills, a measure of visuomotor dexterity, and 2 measures of problem-solving abilities. The MRI data were analyzed in a group x tissue x hemisphere x region analysis of variance. Spearman rho correlations were computed within the hydrocephalus group between the MRI and cognitive measures. RESULTS: Children with hydrocephalus showed reductions in overall gray matter percentages and corresponding increased CSF percentages that were more pronounced in posterior than anterior regions of both hemispheres. White matter percentages were reduced in children with hydrocephalus only in the left posterior quadrant. Correlations of posterior, but not anterior, CSF and gray matter percentages were significant with verbal and performance IQ scores and language, visuospatial, and visuomotor dexterity skills, but not with problem-solving abilities. Children with hydrocephalus who had proportionately greater posterior than anterior CSF percentages had significantly poorer visuomotor dexterity and visuospatial skills than did hydrocephalic children with proportionate CSF percentages. CONCLUSION: Regional variations in brain tissue composition in children with shunted hydrocephalus correlate with a variety of cognitive and visuomotor functions.

Morphometric evaluation of the hydrocephalic brain: relationships with cognitive development.

The effects of early hydrocephalus and related brain anomalies on cognitive skills are not well understood. In this study, magnetic resonance scans were obtained from 99 children aged from 6 to 13 years with either shunted hydrocephalus (n = 42) or arrested (unshunted) hydrocephalus (n = 19), from patient controls with no hydrocephalus (n = 23), and from normal, nonpatient controls (n = 15). Lateral ventricle volumes and area measurements of the internal capsules and centra semiovale in both hemispheres were obtained from these scans, along with area measurements of the corpus callosum. Results revealed reductions in the size of the corpus callosum in the shunted hydrocephalus group. In addition, lateral ventricle volumes were larger and internal capsule areas were smaller in both hemispheres in children with shunted and arrested hydrocephalus. The centra semiovale measurements did not differentiate the groups. Correlating these measurements with concurrent assessments of verbal and nonverbal cognitive skills, motor abilities, and executive functions revealed robust relationships only between the area of the corpus callosum and nonverbal cognitive skills and motor abilities. These results support the theory of a prominent role for the corpus callosum defects characteristic of many children with shunted hydrocephalus in the spatial cognition deficits commonly observed in these children.

Memory tests distinguish between patients with focal temporal and extratemporal lobe epilepsy.

We examined the ability of preoperative memory performance to distinguish between patients who had been diagnosed as having left (LTLE, n = 31), right (RTLE, n = 37), and extra-(ETLE, n = 17) temporal lobe focal epilepsy. All patients eventually underwent surgical resections. Analyses indicated that the ETLE group performed better than the RTLE group on nonverbal memory measures and better than the LTLE group on verbal memory measures. Discriminant function analyses indicated that use of a combination of measures that assess different aspects of memory were of significant value in distinguishing between patients with focal TLE and ETLE. This approach, as compared the use of single measures, improved classification rates of all three groups. The best single predictor of group membership, an index of verbal learning, yielded a 47% overall correct classification rate, with sensitivities ranging from 25 to 59%, and performed at worse than chance levels in classifying RTLE patients. A multivariate approach, which included an index of verbal and nonverbal learning, incidental nonverbal memory, and consolidation of organized and rote verbal material, yielded a 65% correct classification rate, with sensitivities ranging from 57 to 75%. This compares favorably with the other noninvasive techniques for lateralizing epileptogenic lesions.

Verbal and nonverbal skill discrepancies in children with hydrocephalus: a five-year longitudinal follow-up.

Compared verbal and nonverbal skills of 65 children ages 5 to 7 years, with a history of shunted hydrocephalus (n = 26), arrested hydrocephalus (n = 11), and no hydrocephalus (n = 28), over a 5-year period. Comparison of these skills in 4 assessments revealed poorer average nonverbal than verbal skills on measures from the McCarthy Scales of Children's Abilities, the Wechsler Intelligence Scales for Children-Revised (WISC-R), and composites of neuropsychological skills for the shunted hydrocephalus group in comparison to the arrested-hydrocephalus and no hydrocephalus groups. There were higher rates of significant discrepancies between WISC-R Verbal IQ (VIQ) and Performance IQ (PIQ), with PIQ < VIQ in the shunted group. However, relatively few children exhibited significant discrepancies on multiple test occasions. The poorer performance of the shunted hydrocephalus group could not be attributed to motor demands of the nonverbal tasks.

Behavioral adjustment of children with hydrocephalus: relationships with etiology, neurological, and family status.

Examined the relationship of hydrocephalus and behavioral adjustment in three groups of 5- to 7-year-old children (N = 84) with a history of early hydrocephalus (spina bifida, prematurity, aqueductal stenosis) and three non-hydrocephalic comparison groups (spina bifida, prematurity, normals). Results revealed no significant group differences on measures of behavioral adjustment and a variety of family and sociodemographic variables. Children with hydrocephalus were more likely to meet criteria for behavior problems, obtained lower scores on measures of adaptive behavior, and perceived themselves as less physically competent. Categorical modeling analyses showed that hydrocephalus and its treatment, gender, family variables, and motor skills were related to the presence of behavior problems.