Language regression in childhood.

Language regression is observed both in autistic regression and as part of acquired epileptic aphasia (Landau-Kleffner Syndrome). We prospectively identified 177 children with language regression at four major medical centers, and their clinical characteristics were recorded. Their mean age at regression was 22.8 months. The mean time-to-specialist referral was 38 months of age. Most children (88%) met criteria for autism or manifested autistic features. Males (P = 0.02) and children less than 3 years of age who regressed (P = 0.016) had a higher probability of developing autistic behaviors. Seizures were more common in children who regressed after they reached 3 years of age (P < 0.001), and children with seizures were less likely to have associated autistic regression (P < 0.001). Electroencephalogram abnormalities were reported in 37% of patients and were more common in children with seizures (P < 0.001). At last follow-up, language function was impaired in 88% of the children, although some improvement was noted in 57%. We conclude that the loss of previously acquired language at any age, even if that language only includes a few words or communicative gestures, is often associated with a more global regression in cognition and/or behavior and has serious implications for future function. Early identification and referral of these children is necessary to allow for diagnosis and intervention.

Serum autoantibodies to brain in Landau-Kleffner variant, autism, and other neurologic disorders.

OBJECTIVE: Etiologically unexplained disorders of language and social development have often been reported to improve in patients treated with immune-modulating regimens. Here we determined the frequency of autoantibodies to brain among such children. DESIGN: We collected sera from a cohort of children with (1) pure Landau-Kleffner syndrome (n = 2), (2) Landau-Kleffner syndrome variant (LKSV, n = 11), and (3) autistic spectrum disorder (ASD, n = 11). None had received immune-modulating treatment before the serum sample was obtained. Control sera (n = 71) were from 29 healthy children, 22 with non-neurologic illnesses (NNIs), and 20 children with other neurologic disorders (ONDs). We identified brain autoantibodies by immunostaining of human temporal cortex and antinuclear autoantibodies using commercially available kits. RESULTS: IgG anti-brain autoantibodies were present in 45% of sera from children with LKSV, 27% with ASD, and 10% with ONDs compared with 2% from healthy children and control children with NNIs. IgM autoantibodies were present in 36% of sera from children with ASD, 9% with LKSV, and 15% with ONDs compared with 0% of control sera. Labeling studies identified one antigenic target to be endothelial cells. Antinuclear antibodies with titers >/=1:80 were more common in children with ASD and control children with ONDs. CONCLUSION: Children with LKSV and ASD have a greater frequency of serum antibodies to brain endothelial cells and to nuclei than children with NNIs or healthy children. The presence of these antibodies raises the possibility that autoimmunity plays a role in the pathogenesis of language and social developmental abnormalities in a subset of children with these disorders.

Primary motor cortex reorganization in a long-term monkey amputee.

The primary motor cortex (M1) was mapped with intracortical microstimulation (ICMS) in a 15 year-old macaque whose right upper extremity was amputated at the shoulder joint prior to 2 years of age. Movements of the right shoulder girdle and stump were evoked by ICMS throughout the left M1 upper extremity region. The size of the left M1 upper extremity region contralateral to the amputated arm was not appreciably different from the size of the right upper extremity region contralateral to the intact arm. Long stimulus trains and/or higher stimulus currents were needed to evoke detectable movements at significantly more loci in the left than in the right M1 upper extremity region. These observations would be consistent with unmasking of a high threshold representation of shoulder musculature that normally exists throughout the central core of the upper extremity region, where it underlies a lower threshold representation of the distal forelimb. Alternatively, invasion of the de-efferented distal forelimb core by surrounding shoulder representation may have occurred. Differences between the limited M1 reorganization observed in the present study and the more extensive reorganization of S1 observed in other studies may reflect fundamental differences between M1 and S1, and/or differences in the extent of de-efferentation versus deafferentation.

Stimulus cancellation by macaques with unilateral frontal or parietal lesions.

Monkeys' spontaneous behaviors in cancelling a variety of visual and somatosensory stimuli were measured before, and acutely after, unilateral periarcuate (N = 16) and inferior parietal (n = 14) cortical removals. Postoperative behavior was analyzed for both severity of change from the preoperative baseline, and for the type of behavior (perceptual or premotor) affected by the lesion. Overall the two lesion groups could not be differentiated by severity or type of deficit. In two tasks, premotor deficits, manifest as extreme disuse of the hand contralateral to the lesion, were significantly worse in the parietal than the frontal group. In a third, the frontal group showed a greater perceptual deficit, manifest as marked preference for acting within ipsilesional space, than the parietal. In the three remaining tasks, premotor and perceptual deficits were equal in the two groups. These quantitative behavioral data suggest that deficits are more highly contingent upon task requirements than upon lesion sites. This in turn suggests that frontal and parietal association cortical fields each play multiple, and sometimes interchangeable, roles in the spatially directed attention and motor behavior of the monkey.

The functional anatomy of manual motor behavior after unilateral frontal lobe lesions.

In normal brains different behavioral tasks lead to increased metabolism in different loci. Resting monkeys with acute hemineglect following periarcuate lesions show deficient glucose utilization (LCGU) in motor thalamus and other loci of the hemisphere with the lesion. To determine if the abnormal LCGU could be altered by a specific behavioral task, we used behavioral testing and training, and quantitative 2-deoxyglucose (2-DG) autoradiography. Animals reached criterion in a bimanual traction task (BMTT), then were tested for hand preference and responses to sensory stimuli, and received unilateral frontal or sham lesions. Operated animals showed hemineglect, and, on BMTT, intermanual coordination errors. 2-DG of frontals at rest showed deficient LCGU in 4 of 7 thalamic, and 1 of 4 cortical regions assessed. In contrast, only 2 thalamic and no cortical regions were deficient in pulling animals. Thus, in the face of structural damage and distant deficient neural activation, performance of a specific behavioral task may increase metabolism in specific brain loci, implying that plasticity of neural activation vis-a-vis behavioral demand is present even acutely after brain injury.

Developmental manual dyspraxia: a lesson in mind and brain.

For decades, pediatricians assiduously documented "soft neurologic signs" in children referred for school learning difficulties, although pediatric neurologists, including Charles F. Barlow, pointed out the dissociation between most neuropsychological abnormalities and the motor findings in question. Later, large epidemiologic studies confirmed the independence of soft signs from other neuropsychological defects. We used a standardized dyspraxia battery to study 164 schoolchildren 5 to 12 years old. We found that in the group as a whole there was a positive correlation between motor performance in the dyspraxia battery and IQ on the Wechsler Intelligence Scale for Children--revised (Full-Scale, Verbal, and Performance). In terms of dyspraxia subscales, we found that Performance IQ and Full-Scale IQ correlated with imitation of nonsense gestures and use of actual objects, whereas Verbal IQ correlated positively only with pantomime on command. In contrast, for the group of 24 subjects whose scores on the battery designated them as dyspraxic, there was no correlation between dyspraxia scores and IQ. Together with the existence of specific, dramatically different, types of dyspraxia among the 24 dyspraxic subjects, present findings uphold the earlier neurologic opinion that "motor soft signs" are not evidence for fixed "brain damage" or even for other types of motor dysfunction, and that dissociation of different specific cognitive dysfunctions is the rule within individual patients.

Simultaneous in vivo monitoring of cerebral deoxyglucose and deoxyglucose-6-phosphate by 13C[1H] nuclear magnetic resonances spectroscopy.

The capacity of brain to dephosphorylate glucose-6-phosphate has been established, but the magnitude and significance of this capacity in vivo are debated, particularly in regard to dephosphorylation of the glucose analog 2-deoxyglucose. We now report results of external measurement in the brains of conscious rats with simultaneous resolution and quantification of both 2-deoxyglucose and its phosphorylated product by nuclear magnetic resonance (NMR) techniques that used 2-[6-13]deoxyglucose together with proton-decoupled 13C surface-coil spectroscopy. As NMR techniques require large doses of 2-deoxyglucose, a dose comparison was first made using decay curves of total label after tracer doses of 2-[14C]deoxyglucose without versus with unlabeled deoxyglucose at 500 mg/kg (the NMR dose). Similar cerebral half-lives for the two doses were found, and no behavioral evidence for toxicity of the NMR dose was seen. In vivo NMR monitoring of conscious rats showed that the analog reached maximal cerebral concentration within 10 min of the intravenous bolus and decayed with a half-life of 29 +/- 7 min (n = 4; mean +/- SEM), whereas 2-deoxyglucose-6-phosphate reached peak concentration between 30 and 40 min and decayed with a half-life of 2.1 +/- 0.3 h, equivalent to a fractional loss of 0.8%/min. Thirty-one percent (+/- 5%) of the total analog pool (which showed a half-life of 1.4 h) consisted of 2-deoxyglucose at 45 min after the bolus. The results support an active but limited role for dephosphorylation by normal brain in glucose analog (and potentially glucose) metabolism in the unstimulated conscious rat and a wide concentration range for the metabolic operations involved.

Monitoring the time course of cerebral deoxyglucose metabolism by 31P nuclear magnetic resonance spectroscopy.

The phosphorylation of 2-deoxyglucose by the mammalian brain is used as an index of the brain's energy metabolism. The results of phosphorus-31 nuclear magnetic resonance (31P NMR) monitoring of conscious animals in vivo showed rapid phosphorylation of 2-deoxyglucose by brain tissue. The rate of phosphorylation as determined by 31P NMR was consistent with results achieved by tracer methods using carbon-14-labeled 2-deoxyglucose. However, the disappearance of 2-deoxyglucose-6-phosphate was shown to be faster than that reported by tracer studies and occurred without alterations of intracellular pH and energy homeostasis. These results were confirmed by gas chromatography and mass spectroscopy. It is postulated that 2-deoxyglucose may be metabolized in several ways, including dephosphorylation by a hexose phosphatase.

Parietal hemineglect and motor deficits in the monkey.

To study the parietal hemineglect syndrome, we trained and operated nine Macaca fasicularis monkeys. Contralateral to the lesion they showed response abnormalities to visual and somatic sensory stimuli, and misreaching toward targets in visual space, abberant finger and wrist postures and lack of pincer grasp. The latter did not appear during performance of a preoperatively practised task, nor depend for severity upon lesion size, whereas sensory response abnormalities did. We conclude that abnormal motor patterns are separable from hemineglect in parietal animals, and are worst when the movement is directed to a visual target in extrapersonal space.

The functional anatomy of frontal lobe neglect in the monkey: behavioral and quantitative 2-deoxyglucose studies.

A syndrome of hemisensory neglect follows damage to frontal association areas in monkeys and humans. To study the syndrome we removed frontal association cortex from the right hemisphere of macaque monkeys. After operation, behavioral testing showed conditional deficits in visual, somatosensory, and motor responses contralateral to the lesion. Brains of animals were studied with [14C]2-deoxyglucose autoradiography to evaluate functional neuroanatomical changes. Ipsilateral striatal and selected thalamic and midbrain nuclei exhibited depression of glucose utilization (10 to 60%). No consistent glucose utilization changes appeared in cortex or in primary motor or sensory pathways. Brains from unoperated control animals did not exhibit these changes, nor did brains from operated animals with behavioral recovery from neglect. We conclude that the symptoms of frontal lobe neglect in the monkey are the result of dysfunction within a widely distributed system of subcortical centers. The distribution of the dysfunction provides an explanation for some of the clinical features of neglect.

Phosphorus-31 NMR of rat brain in vivo with bloodless perfluorocarbon perfused rat.

Rat brain in vivo has been examined by 31P NMR under conditions of normal blood perfusion (hematocrit 38%) and under conditions in which a perfluorocarbon blood substitute, devoid of any phosphorus containing compounds, largely replaced the animal's normal blood supply (hematocrit 7%). These studies demonstrate that 2,3-diphosphoglycerate does not - as has been suggested - contribute to, and thus does not interfere with, the 31P NMR analysis of rat brain in vivo. However, low intensity 31P resonances assigned to choline phosphate, glycerol 3-phosphorylethanolamine, and glycerol 3-phosphorylcholine are observed. "High energy phosphorus" metabolite levels show no marked change over two hours with perfluorocarbon blood substitution from those of the normal blood perfused animal. This supports use of perfluorocarbon media for tissue perfusion in vitro and for 19F NMR vascular imaging in vivo.

Recovery from unilateral neglect.

Spontaneous recovery of function occurs in the syndrome of hemisensory neglect in monkeys. We produced this syndrome in 13 macaques by unilateral operative resection of the frontal polysensory association cortex. Using standardized behavioral measures, we documented severe acute neglect and followed the course of its improvement. Using the 2-deoxy[14C]glucose autoradiographic method, we studied animals in the acute phase of neglect and found decrements in local glucose utilization in subcortical structures, but not in cortical regions with known frontal connections. After spontaneous behavioral recovery, mild local glucose utilization decrements remained, but only in nucleus medialis dorsalis of the thalamus. The findings suggest that acute behavioral symptoms are based on widespread depression of neuronal activity in uninjured structures with synaptic relations to damaged cortex, and that return of neuronal activity in those structures is accompanied by restitution of behavioral function.

Cerebral dominance and cerebral asymmetries on computed tomogram in childhood.

Hand preference assessment and computed tomography (CT) were used in 94 children to determine whether cerebral morphologic asymmetries were closely correlated with handedness, as reported for adults. We found that parent-reported hand preference and tested hand preference were highly correlated. Eighty-two percent of the CTs showed asymmetry between the hemispheres, but there was no significant correlation between hemispheric configuration and any measure of handedness. Although there may be a statistical relationship between cerebral configuration and handedness in large groups of subjects, hemispheric asymmetries found on routine CT of the head cannot serve as predictors of cerebral dominance in children.