Correction: Brain structure in pediatric Tourette syndrome.

In this published article, members of 'The Tourette Association of America Neuroimaging Consortium' were not cited in PubMed. These consortium members are listed in the associated correction.

Brain structure in pediatric Tourette syndrome.

Previous studies of brain structure in Tourette syndrome (TS) have produced mixed results, and most had modest sample sizes. In the present multicenter study, we used structural magnetic resonance imaging (MRI) to compare 103 children and adolescents with TS to a well-matched group of 103 children without tics. We applied voxel-based morphometry methods to test gray matter (GM) and white matter (WM) volume differences between diagnostic groups, accounting for MRI scanner and sequence, age, sex and total GM+WM volume. The TS group demonstrated lower WM volume bilaterally in orbital and medial prefrontal cortex, and greater GM volume in posterior thalamus, hypothalamus and midbrain. These results demonstrate evidence for abnormal brain structure in children and youth with TS, consistent with and extending previous findings, and they point to new target regions and avenues of study in TS. For example, as orbital cortex is reciprocally connected with hypothalamus, structural abnormalities in these regions may relate to abnormal decision making, reinforcement learning or somatic processing in TS.

Distinct Stages of Moment-to-Moment Processing in the Cinguloopercular and Frontoparietal Networks.

Control of goal-directed tasks is putatively carried out via the cinguloopercular (CO) and frontoparietal (FP) systems. However, it remains unclear whether these systems show dissociable moment-to-moment processing during distinct stages of a trial. Here, we characterize dynamics in the CO and FP networks in a meta-analysis of 5 decision-making tasks using fMRI, with a specialized "slow reveal" paradigm which allows us to measure the temporal characteristics of trial responses. We find that activations in left FP, right FP, and CO systems form separate clusters, pointing to distinct roles in decision-making. Left FP shows early "accumulator-like" responses, suggesting a role in pre-decision processing. CO has a late onset and transient response linked to the decision event, suggesting a role in performance reporting. The majority of right FP regions show late onsets with prolonged responses, suggesting a role in post-recognition processing. These findings expand upon past models, arguing that the CO and FP systems relate to distinct stages of processing within a trial. Furthermore, the findings provide evidence for a heterogeneous profile in the FP network, with left and right FP taking on specialized roles. This evidence informs our understanding of how distinct control networks may coordinate moment-to-moment components of complex actions.

Functional network dysfunction in anxiety and anxiety disorders.

A recent paradigm shift in systems neuroscience is the division of the human brain into functional networks. Functional networks are collections of brain regions with strongly correlated activity both at rest and during cognitive tasks, and each network is believed to implement a different aspect of cognition. We propose here that anxiety disorders and high trait anxiety are associated with a particular pattern of functional network dysfunction: increased functioning of the cingulo-opercular and ventral attention networks as well as decreased functioning of the fronto-parietal and default mode networks. This functional network model can be used to differentiate the pathology of anxiety disorders from other psychiatric illnesses such as major depression and provides targets for novel treatment strategies.

The Human Connectome Project: a data acquisition perspective.

The Human Connectome Project (HCP) is an ambitious 5-year effort to characterize brain connectivity and function and their variability in healthy adults. This review summarizes the data acquisition plans being implemented by a consortium of HCP investigators who will study a population of 1200 subjects (twins and their non-twin siblings) using multiple imaging modalities along with extensive behavioral and genetic data. The imaging modalities will include diffusion imaging (dMRI), resting-state fMRI (R-fMRI), task-evoked fMRI (T-fMRI), T1- and T2-weighted MRI for structural and myelin mapping, plus combined magnetoencephalography and electroencephalography (MEG/EEG). Given the importance of obtaining the best possible data quality, we discuss the efforts underway during the first two years of the grant (Phase I) to refine and optimize many aspects of HCP data acquisition, including a new 7T scanner, a customized 3T scanner, and improved MR pulse sequences.

Automated method for extracting response latencies of subject vocalizations in event-related fMRI experiments.

For functional magnetic resonance imaging studies of the neural substrates of language, the ability to have subjects performing overt verbal responses while in the scanner environment is important for several reasons. Most directly, overt responses allow the investigator to measure the accuracy and reaction time of the behavior. One problem, however, is that magnetic resonance gradient noise obscures the audio recordings made of voice responses, making it difficult to discern subject responses and to calculate reaction times. ASSERT (Adaptive Spectral Subtraction for Extracting Response Times), an algorithm for removing MR gradient noise from audio recordings of subject responses, is described here. The signal processing improves intelligibility of the responses and also allows automated extraction of reaction times. The ASSERT-derived response times were comparable to manually measured times with a mean difference of -8.75 ms (standard deviation of difference = 26.2 ms). These results support the use of ASSERT for the purpose of extracting response latencies and scoring overt verbal responses.

Postictal cerebrospinal fluid abnormalities in children.

OBJECTIVES: To determine the frequency and characteristics of seizure-induced cerebrospinal fluid (CSF) abnormalities in children and to identify potential alternative causes of these findings. METHODS: Consecutive patients (n = 80) who underwent lumbar puncture within 24 hours after a seizure were studied retrospectively. The presence of CSF abnormalities in total leukocytes, polymorphonuclear cells, and protein was determined by using age-specific reference values. Coexisting conditions that could affect CSF findings, such as traumatic lumbar puncture, concurrent neurologic disease, and undiagnosed meningitis, were identified. RESULTS: Eighteen of the 80 patients were excluded from the final study group because of the presence of another condition that could alter the CSF. More than 50% of the excluded patients had an abnormal CSF leukocyte count or protein level, including 2 patients with initially undiagnosed meningitis, which was subsequently detected by post-hoc polymerase chain reaction testing. In the remaining 62 patients, postictal pleocytosis was detected in only 3 (5%), and increased protein was detected in only 6 (10%). The maximal postictal pleocytosis and protein level were 8 x 10(6) leukocytes/L (8 leukocytes/mm(3)) and 0.52 g/L (52 mg/dL), respectively. CONCLUSIONS: Seizure-induced CSF abnormalities are rare in children, and alternative, often unidentified, disease processes may account for many observed postictal abnormalities. All patients with abnormal CSF after a seizure should be thoroughly evaluated for other causes of the abnormality.

Cerebrospinal fluid protein concentration in pediatric patients: defining clinically relevant reference values.

OBJECTIVES: To define clinically relevant reference ("normal") values for cerebrospinal fluid (CSF) protein concentrations in pediatric patients who were evaluated for meningitis by traditional criteria and by enterovirus-polymerase chain reaction (EV-PCR). DESIGN AND PATIENTS: A cohort of 906 consecutive pediatric patients to receive CSF analysis at St Louis Children's Hospital, St Louis, Mo, from June 1, 1998, to December 31,1998, was studied for clinical and laboratory data. Age-dependent CSF protein concentrations were then derived from a reference group of 225 patients in whom meningitis and other neurologic diseases were excluded by traditional clinical or laboratory criteria (excluding EV-PCR). Available CSF samples from 132 patients of the reference group were subsequently tested for EV-PCR. RESULTS: In the reference group, the CSF protein concentration was highest and most variable in neonates, with a maximum of approximately 1.0 g/L. Cerebrospinal fluid protein concentration decreased rapidly to a nadir by 6 months and remained low throughout childhood, rarely exceeding 0.3 g/L and, finally, increasing in adolescence toward adult values. Enterovirus- polymerase chain reaction was positive in CSF of 11% of the reference group, with EV-PCR-positive patients having significantly higher CSF protein concentrations than EV-PCR-negative patients aged between 4 months and 14 years. CONCLUSIONS: Reference values for CSF protein exhibit a characteristic age dependence in pediatric patients. Continued standard use of adult reference values in the pediatric population is inappropriate. The unexpected finding of a positive EV-PCR in patients not diagnosed with meningitis by traditional criteria further emphasizes the importance of selecting the most clinically relevant reference group for age and other variables when defining normal laboratory values. Arch Pediatr Adolesc Med. 2000;154:827-831

A 16-year-old with episodic hemisdystonia.

The paroxysmal dyskinesias are a subset of the hyperkinetic movement disorders characterized by their episodic nature. Classification based on precipitating factors is helpful in considering treatment and prognosis. The clinical similarities with partial seizures are discussed. An approach to differential diagnosis, diagnostic evaluation, and treatment options are presented.

Glutamate receptor blockade at cortical synapses disrupts development of thalamocortical and columnar organization in somatosensory cortex.

The segregation of thalamocortical inputs into eye-specific stripes in the developing cat or monkey visual cortex is prevented by manipulations that perturb or abolish neural activity in the visual pathway. Such findings show that proper development of the functional organization of visual cortex is dependent on normal patterns of neural activity. The generalisation of this conclusion to other sensory cortices has been questioned by findings that the segregation of thalamocortical afferents into a somatotopic barrel pattern in developing rodent primary somatosensory cortex (S1) is not prevented by activity blockade. We show that a temporary block of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors in rat S1 during the critical period for barrel development disrupts the topographic refinement of thalamocortical connectivity and columnar organization. These effects are evident well after the blockade is ineffective and thus may be permanent. Our findings show that neural activity and specifically the activation of postsynaptic cortical neurons has a prominent role in establishing the primary sensory map in S1, as well as the topographic organization of higher order synaptic connections.

Maturation-dependent upregulation of growth-promoting molecules in developing cortical plate controls thalamic and cortical neurite growth.

We have tested the hypothesis that maturation-dependent changes in the cortical plate affect the spatiotemporal growth patterns of developing thalamocortical and corticocortical axonal projections. Given a choice between alternating lanes of embryonic (E18-19) and neonatal (P0-1) rat cortical plate membranes, embryonic (E18-19) thalamic and cortical neurites prefer to extend on neonatal membranes. Thalamic and cortical explants do extend neurites on uniform carpets of E19 cortical plate membranes, but the outgrowth is consistently greater on uniform carpets of P1 cortical plate membranes. These experiments demonstrate a maturation-dependent enhancement in the ability of cortical plate to support neurite growth from thalamic and cortical explants. In contrast, retinal and cerebellar neurites, which do not grow into cortex in vivo, generally grew poorly on these membranes, suggesting a degree of specificity to the neurite growth response. Immunohistochemical analysis of developing cortex suggests that several extracellular matrix (ECM) and cell adhesion molecules are upregulated in cortical plate. However, immunocharacterization of membrane carpets for these same ECM and cell adhesion molecules suggests that the growth preferences of thalamic and cortical neurites in vitro are predominantly influenced by membrane-anchored, rather than ECM, molecules. Western analysis of E19 and P1 cortical plate membranes supports this conclusion, and indicates that the membrane-anchored cell adhesion molecules L1 and N-CAM are more abundant in the P1 cortical plate membrane preparation. Experiments in which cortical plate membranes were treated to remove molecules sensitive to phosphatidylinositol (PI)-specific phospholipase C demonstrate that neurite growth promoters present in E19 cortical plate membranes are predominantly PI linked, whereas those present in P1 membranes are predominantly non-PI linked. These findings indicate that the neurite growth preferences are mediated, at least in part, by an upregulation of neurite growth-promoting molecules in developing cortical plate that are not PI linked. Taken together, these findings suggest that a maturation-dependent upregulation of neurite growth-promoting molecules on cortical plate cells controls the invasion of the cortical plate by thalamocortical and corticocortical axons.

Development of acetylcholinesterase-positive thalamic and basal forebrain afferents to embryonic rat neocortex.

By combining anterograde and retrograde axonal tracing with AChE histochemistry, we demonstrate the sources of AChE-positive afferents to embryonic neocortex, the pathways they use, their time of arrival into cortex, and their initial invasion of the cortical plate. Acetylcholinesterase (AChE) is expressed by two populations of cortical afferents: AChE is permanently present in basal forebrain fibers and has been reported to be transiently localized in axons of the principal sensory thalamic nuclei over the first few postnatal weeks beginning at the middle of the first week. We first detect AChE-positive afferents histochemically in neocortex on embryonic day seventeen (E17) and determine that they arise from the principal sensory thalamic nuclei. AChE histochemistry labels the entire length of developing thalamocortical axons, including their growth cones and branches. These AChE-positive afferents enter the neocortex by the internal capsule and take an intracortical pathway centered on the subplate layer. As soon as these axons are detected, some have already begun to extend AChE-positive collateral branches superficially toward the cortical plate. By E19, a few collaterals have entered the deep part of the cortical plate and by E21 have densely invaded all but its most superficial undifferentiated part. AChE-positive afferents from basal forebrain structures reach the neocortex by three routes: the external capsule, the internal capsule, and the cingulate bundle. Among basal forebrain components, only the substantia innominata and nucleus basalis of Meynert reach the cortex by the internal capsule. Afferents from these two sources reach neocortex on E18, but are a very minor component of the total population of AChE-positive afferents at this age. Afferents from other basal forebrain components do not reach neocortex until several days later. The spatial and temporal patterns of AChE expression in developing thalamocortical axons indicate that it is useful for delineating their innervation of the primary sensory areas of embryonic neocortex, and suggest that AChE may function in axon extension and cortical differentiation.

Plasticity in the development of neocortical areas.

Heterotopic transplantation analysis suggests that individual areas of the developing neocortex have the capacity to differentiate many of the architectural and connectional features normally characteristic of other neocortical areas. Many studies indicate a pivotal role for thalamocortical afferents in the differentiation of the area-specific features that distinguish neocortical areas. Both activity-dependent and activity-independent mechanisms contribute to the patterning of thalamocortical afferent terminations. The available evidence suggests that positional information is established in the cortical subplate and that this information controls the precise targeting of developing thalamocortical axons. In this way appropriate thalamocortical relationships can be established that allow these afferents to promote the differentiation of the functionally specialized and anatomically distinct areas of the adult neocortex.

Early development of the somatotopic map and barrel patterning in rat somatosensory cortex.

Several lines of evidence implicate a crucial role for thalamic afferents from the ventroposterior nucleus (VP) in the development of barrels and their characteristic pattern in the primary somatosensory cortex (S1) of rodents. We sought to determine the stage in development when VP thalamocortical afferents are first distributed in a periphery-related pattern and the sequence of events that culminate in a mature pattern. Using acetylcholinesterase (AChE) histochemistry, an early marker for VP thalamocortical afferents, and the anterograde axon tracer DiI, we show that VP thalamocortical afferents become distributed into a periphery-related pattern earlier than was previously reported, including their parcellation into a barrel-related pattern that mirrors the distribution of sensory hairs on the face. The earliest periphery-related patterning observed is transiently present in the deep cortical layers prior to the emergence of layer 4, the layer in which barrels later develop. AChE histochemistry reveals a clear sequence of maturation of the barrel pattern in the distribution of VP afferents: An initially patternless distribution of AChE-reactive afferents is followed by their distribution in a nascent trigeminal representation, from which rows subsequently emerge; barrel-related clusters of afferents then emerge from the rows. This process begins before birth, and the transition from row-related to barrel-related distributions of VP afferents is evident during the first postnatal day (P0). This demonstration of a periphery-related pattern in developing rat S1 precedes by about 2 days that revealed by any other marker reported to delineate barrels. These findings confirm that VP thalamocortical afferents are the first barrel component to have a periphery-related pattern and support the hypothesis that thalamocortical afferents provide to immature S1 the patterning information that initiates the formation of barrels and their characteristic array. Furthermore because these findings show an earlier onset for barrel formation than was previously realized, they necessitate a reevaluation of conclusions drawn from experiments examining developmental plasticity in barrel patterning.

Acetylcholinesterase as an early marker of the differentiation of dorsal thalamus in embryonic rats.

The enzyme acetylcholinesterase (AChE) is transiently expressed in rats by neurons of the principal sensory thalamic nuclei, although these neurons do not use acetylcholine as a neurotransmitter. Reports that AChE expression begins at late embryonic stages led to the proposal that AChE may function in the establishment of connections, but not in earlier events. However, we find AChE reactivity in rat dorsal thalamus 5 days earlier than previously described. Cells that form the ventrobasal complex (VB), the dorsal lateral geniculate nucleus (dLG) and the medial geniculate nucleus, express AChE as they migrate and aggregate into definitive nuclei. AChE-positive cells are occasionally observed in the dorsal thalamic neuroepithelium, but are more common in others regions of the diencephalic neuroepithelium. AChE reactivity delineates VB and dLG earlier than Nissl-stained cytoarchitecture. These findings indicate that AChE is an early marker of neuronal differentiation. Certain properties of AChE, together with its early detection, are consistent with a proposed role in the migration of principal sensory neurons and their organization into discrete nuclei.

Postsynaptic control of plasticity in developing somatosensory cortex.

The rearrangement of synaptic connections during normal and deprived development is though to be controlled by correlations in afferent impulse activity. A favoured model is based on post-synaptic detection of synchronously active afferents; synapses are stabilized when pre- and postsynaptic activity is correlated and weakened or eliminated when their activity is uncorrelated. Most evidence for this model comes from demonstrations that correlated afferent input is necessary for the segregation of eye-dominant inputs in the developing vertebrate visual system and that critical period plasticity of ocular dominance columns in cat visual cortex is disrupted by blockade of postsynaptic transmission. We tested whether the developmental plasticity of somatosensory columns, known as 'barrels', in rodent primary somatosensory cortex (S1) is similar to that of ocular dominance columns. We report here that the selective disruption of postsynaptic activation in rat S1 by application of a glutamate receptor antagonist inhibits rearrangements in the somatotopic patterning of thalamocortical afferents induced by manipulations of the sensory periphery during the critical period. These findings show that postsynaptic activation has a prominent role in critical period plasticity in S1 cortex.

Patterning of the barrel field in somatosensory cortex with implications for the specification of neocortical areas.

The adult neocortex, a distinct region of the mammalian cerebral cortex, is characterized by numerous anatomically and functionally distinct areas. Many of the connectional and architectural features that distinguish areas in the adult neocortex are not evident in the immature neocortex. A central issue in understanding neocortical area differentiation is determining the relative contributions of genetic and epigenetic factors in the emergence of area-specific features during neocortical development. A model system for this issue has been the rodent somatosensory cortex, which uniquely contains "barrels," anatomically evident functional groupings of cortical neurons and thalamocortical afferents that, in the tangential plane of cortex, are arranged in a pattern that reflects the distribution of vibrissae on the rodent body surface. Here, we address the role of thalamocortical afferents in the differentiation of barrels and their patterning in the context of discussing the specification of neocortical areas.

The specification of sensory cortex: lessons from cortical transplantation.

The mammalian neocortex is functionally organized into numerous specialized "areas." The distinct functional properties characteristic of each area are in large part due to connectional and architectural differences among the areas. However, these "area-specific" features which distinguish mature areas are not apparent early in the development of neocortex. We have used heterotopic cortical transplantation to examine whether these area-specific features are prespecified or emerge as a result of epigenetic interactions. Here, we review our studies in which late fetal rat cortex was transplanted heterotopically into the cortex of newborn rats to test its capacity to differentiate features normally unique to other cortical areas. We find that regions of the developing neocortex have similar potentials to differentiate the connectivity and functional architecture that distinguish neocortical areas in the adult. We conclude that the neocortical neuroepithelium generates comparable populations of cells across its extent, and when exposed to the same extrinsic cues, these populations can differentiate in comparable ways. These studies support the concept that the neocortical neuroepithelium generates a "protocortex" (20), specified to have fundamental cortical features but lacking a rigid specification of "area-specific" features.

Potential of visual cortex to develop an array of functional units unique to somatosensory cortex.

The identification of specialized areas in the mammalian neocortex, such as the primary visual or somatosensory cortex, is based on distinctions in architectural and functional features. The extent to which certain features that distinguish neocortical areas in rats are prespecified or emerge as a result of epigenetic interactions was investigated. Late embryonic visual cortex transplanted to neonatal somatosensory cortex was later assayed for "barrels," anatomically identified functional units unique to somatosensory cortex, and for boundaries of glycoconjugated molecules associated with barrels. Barrels and boundaries form in transplanted visual cortex and are organized in an array that resembles the pattern in the normal barrelfield. These findings show that different regions of the developing neocortex have similar potentials to differentiate features that distinguish neocortical areas and contribute to their unique functional organizations.