Developmental changes in gamma-aminobutyric acid levels in attention-deficit/hyperactivity disorder.

While the neurobiological basis and developmental course of attention-deficit/hyperactivity disorder (ADHD) have not yet been fully established, an imbalance between inhibitory/excitatory neurotransmitters is thought to have an important role in the pathophysiology of ADHD. This study examined the changes in cerebral levels of GABA+, glutamate and glutamine in children and adults with ADHD using edited magnetic resonance spectroscopy. We studied 89 participants (16 children with ADHD, 19 control children, 16 adults with ADHD and 38 control adults) in a subcortical voxel (children and adults) and a frontal voxel (adults only). ADHD adults showed increased GABA+ levels relative to controls (P = 0.048), while ADHD children showed no difference in GABA+ in the subcortical voxel (P > 0.1), resulting in a significant age by disorder interaction (P = 0.026). Co-varying for age in an analysis of covariance model resulted in a nonsignificant age by disorder interaction (P = 0.06). Glutamine levels were increased in children with ADHD (P = 0.041), but there was no significant difference in adults (P > 0.1). Glutamate showed no difference between controls and ADHD patients but demonstrated a strong effect of age across both groups (P < 0.001). In conclusion, patients with ADHD show altered levels of GABA+ in a subcortical voxel which change with development. Further, we found increased glutamine levels in children with ADHD, but this difference normalized in adults. These observed imbalances in neurotransmitter levels are associated with ADHD symptomatology and lend new insight in the developmental trajectory and pathophysiology of ADHD.

Age dependent electroencephalographic changes in attention-deficit/hyperactivity disorder (ADHD).

OBJECTIVE: Objective biomarkers for attention-deficit/hyperactivity disorder (ADHD) could improve diagnostics or treatment monitoring of this psychiatric disorder. The resting electroencephalogram (EEG) provides non-invasive spectral markers of brain function and development. Their accuracy as ADHD markers is increasingly questioned but may improve with pattern classification. METHODS: This study provides an integrated analysis of ADHD and developmental effects in children and adults using regression analysis and support vector machine classification of spectral resting (eyes-closed) EEG biomarkers in order to clarify their diagnostic value. RESULTS: ADHD effects on EEG strongly depend on age and frequency. We observed typical non-linear developmental decreases in delta and theta power for both ADHD and control groups. However, for ADHD adults we found a slowing in alpha frequency combined with a higher power in alpha-1 (8-10Hz) and beta (13-30Hz). Support vector machine classification of ADHD adults versus controls yielded a notable cross validated sensitivity of 67% and specificity of 83% using power and central frequency from all frequency bands. ADHD children were not classified convincingly with these markers. CONCLUSIONS: Resting state electrophysiology is altered in ADHD, and these electrophysiological impairments persist into adulthood. SIGNIFICANCE: Spectral biomarkers may have both diagnostic and prognostic value.

Coupling between resting cerebral perfusion and EEG.

While several studies have investigated interactions between the electroencephalography (EEG) and functional magnetic resonance imaging BOLD signal fluctuations, less is known about the associations between EEG oscillations and baseline brain haemodynamics, and few studies have examined the link between EEG power outside the alpha band and baseline perfusion. Here we compare whole-brain arterial spin labelling perfusion MRI and EEG in a group of healthy adults (n = 16, ten females, median age: 27 years, range 21-48) during an eyes closed rest condition. Correlations emerged between perfusion and global average EEG power in low (delta: 2-4 Hz and theta: 4-7 Hz), middle (alpha: 8-13 Hz), and high (beta: 13-30 Hz and gamma: 30-45 Hz) frequency bands in both cortical and sub-cortical regions. The correlations were predominately positive in middle and high-frequency bands, and negative in delta. In addition, central alpha frequency positively correlated with perfusion in a network of brain regions associated with the modulation of attention and preparedness for external input, and central theta frequency correlated negatively with a widespread network of cortical regions. These results indicate that the coupling between average EEG power/frequency and local cerebral blood flow varies in a frequency specific manner. Our results are consistent with longstanding concepts that decreasing EEG frequencies which in general map onto decreasing levels of activation.

Congenital prosopagnosia: multistage anatomical and functional deficits in face processing circuitry.

Face recognition is a primary social skill which depends on a distributed neural network. A pronounced face recognition deficit in the absence of any lesion is seen in congenital prosopagnosia. This study investigating 24 congenital prosopagnosic subjects and 25 control subjects aims at elucidating its neural basis with fMRI and voxel-based morphometry. We found a comprehensive behavioral pattern, an impairment in visual recognition for faces and buildings that spared long-term memory for faces with negative valence. Anatomical analysis revealed diminished gray matter density in the bilateral lingual gyrus, the right middle temporal gyrus, and the dorsolateral prefrontal cortex. In most of these areas, gray matter density correlated with memory success. Decreased functional activation was found in the left fusiform gyrus, a crucial area for face processing, and in the dorsolateral prefrontal cortex, whereas activation of the medial prefrontal cortex was enhanced. Hence, our data lend strength to the hypothesis that congenital prosopagnosia is explained by network dysfunction and suggest that anatomic curtailing of visual processing in the lingual gyrus plays a substantial role. The dysfunctional circuitry further encompasses the fusiform gyrus and the dorsolateral prefrontal cortex, which may contribute to their difficulties in long-term memory for complex visual information. Despite their deficits in face identity recognition, processing of emotion related information is preserved and possibly mediated by the medial prefrontal cortex. Congenital prosopagnosia may, therefore, be a blueprint of differential curtailing in networks of visual cognition.

Learning to appreciate others: neural development of cognitive perspective taking.

Neuroimaging studies have thoroughly investigated brain regions that are recruited when we put ourselves in another person's shoes. Taking a third-person perspective (3PP) as opposed to a first-person perspective (1PP) has been associated with brain activation in the inferior parietal cortex, the medial posterior cortex and the prefrontal cortex. Here we investigate for the first time the development of the neural network that yields cognitive perspective taking. Twelve adults (aged 25-32 years) and twelve school-aged children (aged 8-10 years) were investigated using functional magnetic resonance imaging (fMRI). Behaviorally, we found a decrease of reaction time differences between 3PP and 1PP with age indicating that adults were more efficient in processing a 3PP. Despite the reaction time differences both groups were equally accurate in their judgments. Brain imaging data indicated neural activity in the left inferior parietal cortex and precuneus for adults during 3PP as compared with 1PP judgments. Children additionally showed enhanced activity in the dorsolateral prefrontal cortex and the right inferior perietal cortex. We found a significant interaction between groups and brain activation in the right dorsolateral prefrontal cortex and in the right inferior parietal cortex. These results suggest that the development of the ability to reason about another person's mind accompanies a shift in activity from frontal to posterior brain regions and from bilateral to unilateral left inferior parietal cortex.

Dysfunctional neural network of spatial working memory contributes to developmental dyscalculia.

The underlying neural mechanisms of developmental dyscalculia (DD) are still far from being clearly understood. Even the behavioral processes that generate or influence this heterogeneous disorder are a matter of controversy. To date, the few studies examining functional brain activation in children with DD mainly focus on number and counting related tasks, whereas studies on more general cognitive domains that are involved in arithmetical development, such as working memory are virtually absent. There are several studies showing a close relationship between DD and spatial working memory [Camos, V. (2008). Low working memory capacity impedes both efficiency and learning of number transcoding in children. Journal of Experimental Child Psychology, 99(1), 37-57; McLean, J. F., & Hitch, G. J. (1999). Working memory impairments in children with specific arithmetic learning difficulties. Journal of Experimental Child Psychology, 74(3), 240-260; Rosselli, M., Matute, E., Pinto, N., & Ardila, A. (2006). Memory abilities in children with subtypes of dyscalculia. Developmental Neuropsychology, 30(3), 801-818; Siegel, L. S., & Ryan, E. B. (1989). The development of working memory in normally achieving and subtypes of learning disabled children. Child Development, 60(4), 973-980]. The relationship between these two mechanisms is still matter of debate, but this study follows the assumption that poor spatial working memory capacity may hinder the acquisition of spatial number representations in children with DD [Geary, D. C. (1993). Mathematical disabilities: Cognitive, neuropsychological, and genetic components. Psychological Bulletin, 114(2), 345-362; von Aster, M., & Shalev, R. S. (2007). Number development and developmental dyscalculia. Developmental Medicine and Child Neurology, 49(11), 868-873]. Using functional MRI the current study compares brain activity associated with spatial working memory processes in 8-10-year-old children with DD and normally achieving controls. Both groups showed significant spatial working memory related activity in a network including occipital and parietal regions. Children with DD showed weaker neural activation compared to the control group during a spatial working memory task in the right intraparietal sulcus (IPS), the right insula and the right inferior frontal lobe. Performance tests outside the scanner showed impaired working memory proficiency in children with DD. Bringing behavioral performance and neural activity together we found significant correlations of right IPS activity with performance on the verbal digit span forward and the spatial Corsi Block Tapping test. Our findings demonstrate for the first time an involvement of spatial working memory processes in the neural underpinnings of DD. These poor spatial working memory processes may inhibit the formation of spatial number representations (mental numberline) as well as the storage and retrieval of arithmetical facts.

Optimized voxel-based morphometry in children with developmental dyscalculia.

Developmental dyscalculia (DD) is a specific learning disability affecting the normal acquisition of arithmetic skills. Current studies estimate that 3-6% of the school population is affected by DD. Genetic, neurobiological, and epidemiologic evidence indicates that dyscalculia is a brain-based disorder. Imaging studies suggest the involvement of parietal and prefrontal cortices in arithmetic tasks. The aim of the present study was to analyze if children with DD show structural differences in parietal, frontal, and cingulate areas compared to typically achieving children. Magnetic resonance imaging was obtained from 12 children with DD aged 9.3+/-0.2 years and 12 age-matched control children without any learning disabilities on a 1.5 T whole-body scanner. Voxel-based morphometry analysis with an optimization of spatial segmentation and normalization procedures was applied to compare the two groups in order to find differences in cerebral gray and white matter. Compared to controls, children with DD show significantly reduced gray matter volume in the right intraparietal sulcus (IPS), the anterior cingulum, the left inferior frontal gyrus, and the bilateral middle frontal gyri. White matter comparison demonstrates clusters with significantly less volume in the left frontal lobe and in the right parahippocampal gyrus in dyscalculic children. The decreased gray and white matter volumes in the frontoparietal network might be the neurological substrate of impaired arithmetic processing skills. The white matter volume decrease in parahippocampal areas may have influence on fact retrieval and spatial memory processing.

Distribution of motor unit potential velocities in short static and prolonged dynamic contractions at low forces: use of the within-subject's skewness and standard deviation variables.

Behaviour of motor unit potential (MUP) velocities in relation to (low) force and duration was investigated in biceps brachii muscle using a surface electrode array. Short static tests of 3.8 s (41 subjects) and prolonged dynamic tests (prolonged tests) of 4 min (30 subjects) were performed as position tasks, applying forces up to 20% of maximal voluntary contraction (MVC). Four variables, derived from the inter-peak latency technique, were used to describe changes in the surface electromyography signal: the mean muscle fibre conduction velocity (CV), the proportion between slow and fast MUPs expressed as the within-subject skewness of MUP velocities, the within-subject standard deviation of MUP velocities [SD-peak velocity (PV)], and the amount of MUPs per second (peak frequency=PF). In short static tests and the initial phase of prolonged tests, larger forces induced an increase of the CV and PF, accompanied with the shift of MUP velocities towards higher values, whereas the SD-PV did not change. During the first 1.5-2 min of the prolonged lower force levels tests (unloaded, and loaded 5 and 10% MVC) the CV and SD-PV slightly decreased and the MUP velocities shifted towards lower values; then the three variables stabilized. The PF values did not change in these tests. However, during the prolonged higher force (20% MVC) test, the CV decreased and MUP velocities shifted towards lower values without stabilization, while the SD-PV broadened and the PF decreased progressively. It is argued that these combined results reflect changes in both neural regulatory strategies and muscle membrane state.

The effect of word concreteness on recognition memory.

Concrete words that are readily imagined are better remembered than abstract words. Theoretical explanations for this effect either claim a dual coding of concrete words in the form of both a verbal and a sensory code (dual-coding theory), or a more accessible semantic network for concrete words than for abstract words (context-availability theory). However, the neural mechanisms of improved memory for concrete versus abstract words are poorly understood. Here, we investigated the processing of concrete and abstract words during encoding and retrieval in a recognition memory task using event-related functional magnetic resonance imaging (fMRI). As predicted, memory performance was significantly better for concrete words than for abstract words. Abstract words elicited stronger activations of the left inferior frontal cortex both during encoding and recognition than did concrete words. Stronger activation of this area was also associated with successful encoding for both abstract and concrete words. Concrete words elicited stronger activations bilaterally in the posterior inferior parietal lobe during recognition. The left parietal activation was associated with correct identification of old stimuli. The anterior precuneus, left cerebellar hemisphere and the posterior and anterior cingulate cortex showed activations both for successful recognition of concrete words and for online processing of concrete words during encoding. Additionally, we observed a correlation across subjects between brain activity in the left anterior fusiform gyrus and hippocampus during recognition of learned words and the strength of the concreteness effect. These findings support the idea of specific brain processes for concrete words, which are reactivated during successful recognition.

Intrasubject reproducibility of presurgical language lateralization and mapping using fMRI.

BACKGROUND: fMRI is becoming a standard tool for the presurgical lateralization and mapping of brain areas involved in language processing. However, its within-subject reproducibility has yet to be fully explored. OBJECTIVE: To evaluate within-test and test-retest reliability of language fMRI in consecutive patients undergoing evaluation for epilepsy surgery. METHODS: Thirty-four unselected patients were investigated once (within-test reliability) and 12 patients twice (test-retest reliability). The imaging series consisted of an alternating 25-second synonym judgment condition with a 25-second letter-matching condition repeated 15 times. Reproducibility of activation maps of the first and second half of session 1 or activation maps of sessions 1 and 2 was evaluated by comparing one global and three regional lateralization indexes (Broca's area, remaining prefrontal cortex, temporoparietal area) and on a voxel-by-voxel basis (intraclass correlation coefficient, percentage overlap, correlation of t-values). RESULTS: Global and regional language lateralization was achieved with high reliability within and across sessions. Reproducibility was evenly distributed across both hemispheres but not within each hemisphere. Frontal activations were more reliable than temporoparietal ones. Depending on the statistical threshold chosen, the voxel-by-voxel analysis revealed a mean overlap of activations derived from the first and second investigation of up to 48.9%. CONCLUSION: Language fMRI proved sufficiently reliable for the determination of global and regional lateralization of language representation in individual unselected patients with epilepsy.

Human memory formation is accompanied by rhinal-hippocampal coupling and decoupling.

In humans, distinct processes within the hippocampus and rhinal cortex support declarative memory formation. But do these medial temporal lobe (MTL) substructures directly cooperate in encoding new memories? Phase synchronization of gamma-band electroencephalogram (EEG) oscillations (around 40 Hz) is a general mechanism of transiently connecting neural assemblies. We recorded depth-EEG from within the MTL of epilepsy patients performing a memorization task. Successful as opposed to unsuccessful memory formation was accompanied by an initial elevation of rhinal-hippocampal gamma synchronization followed by a later desynchronization, suggesting that effective declarative memory formation is accompanied by a direct and temporarily limited cooperation between both MTL substructures.

Language mapping in less than 15 minutes: real-time functional MRI during routine clinical investigation.

Neurosurgical interventions often require the presurgical determination of language dominance or mapping of language areas. Results obtained by fMRI are closely correlated with invasive procedures such as electrical stimulation mapping or the intracarotid amobarbital test. However, language fMRI is not used routinely, because postprocessing is time-consuming. We utilized a real-time analysis software installed directly on the MR console computer and SPM99 as reference postprocessing software. We assessed the reliability of the immediate determination of language dominance based on individual activation maps by comparing the results of the visual analysis of images derived from conventional postprocessing with those produced by the real-time tool. All images were rated independently by six senior neurologists blinded to other data. We validated the robustness of the real-time method statistically by comparing global and regional lateralization indices derived from real-time and postprocessing analysis. Functional MRI was performed with a standard 1.5-T whole-body scanner. Brain activity was contrasted between an alternating semantic judgment and letter matching task. Twelve right-handed, healthy control subjects and 12 consecutive patients with drug-resistant, localization-related epilepsy were investigated. The semantic condition induced almost invariably left hemispheric activations in Broca's area, the premotor cortex, the dorsolateral prefrontal cortex, and the temporoparietal region. Although real-time analysis reduced noise less effectively than SPM99, visual ratings and lateralization indices produced highly concordant results with both methods. In conclusion, real-time fMRI, as used here, allowed reliable language lateralization and mapping in less than 15 min during routine clinical MRI investigation with no need for postprocessing.

Working memory processes show different degrees of lateralization: evidence from event-related potentials.

This study aimed to identify different processes in working memory, using event-related potentials (ERPs) and response times. Abstract polygons were presented for memorization and subsequent recall in a delayed matching-to-sample paradigm. Two polygons were presented bilaterally for memorization and a cue indicated whether one (and if so, which one of the two) or both polygons had to be memorized. A subsequent test figure was presented unilaterally to the left or right visual field and had to be compared with the memorized figure(s). ERP results suggested that memorization takes place in a visual buffer in contralateral posterior brain areas, whereas identification of the test stimulus as a target appears to be mainly a left hemispheric process. Increased response times were found for nontarget test stimuli as compared to targets, and for target test stimuli that were presented contralaterally with respect to the location of the memorized stimulus. In addition, response times were slower when two figures were memorized than when only one was memorized.

An event-related brain potential correlate of visual short-term memory.

Event-related potentials (ERPs) were recorded as 12 subjects performed a delayed matching to sample task. We presented two bilateral abstract shapes and cued spatially which had to be memorized for a subsequent matching task: left, right or both. During memorization a posterior slow negative ERP wave developed over the hemisphere contralateral to the memorized shape. This effect was similar in high and low memory load trials while the memory figures were visible (for 1000 ms). As the figures disappeared (for 1500 ms), the effect persisted only in the low memory load conditions. We suggest that the contralateral negativity reflects a visual short-term memory process and that capacity limitation in the high memory load condition causes this process to collapse.

Representations in human visual short-term memory: an event-related brain potential study.

Behavioral measures and event-related potentials (ERPs) were recorded from 12 subjects while performing three delayed matching-to-sample tasks. The task instructions indicated whether stimulus locations, shapes or conjunctions of locations and shapes had to be memorized and matched against a probe. Memory load was varied trial-by-trial by cueing one or two of three stimuli for memorization, followed by one probe. ERPs during memorization and probe response times varied as a function of memory load (posterior negative and anterior positive ERP wave), but not between single-feature and conjunction of features, nor was an interaction found between them. The results support and extend hypotheses by Luck and Vogel (Luck, S.J. and Vogel, E.K., The capacity of visual working memory for features and conjunctions. Nature, 390 (1997) 279-281.) that visual short-term memory stores conjunctions of features rather than single features.

Calcium balance in Drakensberg crag lizards (Pseudocordylus melanotus melanotus; Cordylidae).

Eight nonreproductive female Drakensberg crag lizards (Pseudocordylus melanotus melanotus) were each fed diets of mealworms and calcium capsules with various calcium levels. Excreta were collected and analyzed for calcium and uric acid content. The amount of calcium in the feces was calculated. The lizards appeared to be able to maintain calcium balance at calcium intakes equivalent to 1.4-5.6% calcium in the dry matter of feed. Calcium balance was maintained by adapting intestinal calcium absorption.

[Tele-immobilization of (gone) wild animals in Dutch veterinary practice. 2: Anesthetics used in the immobilization of wild animals]. / Tele-immobilisatie van (ver)wilde(rde) dieren in de Nederlandse diergeneeskundige praktijk. Deel 2: Anesthetica gebruikt bij de immobilisatie van wilde dieren.

In this article a review will be given of the groups of anaesthetics used for animal capture, their developmental history, mode of action and indication for use. A table with dosages of locally--in the Netherlands--available drugs will be presented for a number of animal species.

[Acute management of patients bitten by poisonous snakes]. / Acute opvang van patiënten gebeten door een gifslang.

The management of poisonous snake bites includes first aid and clinical medical treatment. First aid consists of reassurement of the patient, immobilisation of the bitten limb and rapid transport to the nearest hospital to monitor the vital functions. In no case suction, incision or tight bandages should be applied. The degree of envenomation can be classified in three categories depending on the spread of the symptoms: no symptoms, only local non-progressive symptoms, and systemic or local rapidly progressive symptoms (severe envenomation). Antivenin therapy is indicated in severe envenomation. Because of the risk of anaphylactic reactions or serum sickness, antivenin should be given with great caution. Antibiotic therapy and tetanus prophylaxis are advised in all cases. Immediate consultation with the National Intoxication Centre of the Rijksinstitut voor Volksgezondheid en Milieu (RIVM) is always warranted; telephone: 030-2748888. In a national protocol, which is available at the RIVM, the Harbour Hospital Rotterdam, the Academic Medical Centre and Artis Zoo Amsterdam, the correct management of snake bites is described. An overview of all antivenins available in the Netherlands is also given in this protocol.

[Remote anaesthesia of animals in veterinary practice in the Netherlands]. / Tele-immobilisatie van [ver]wilde[rde] dieren in de nederlandse diergeneeskundige praktijk. Artikel 1: tele-injectiesystemen.

In a series of three review articles different aspects of wild animal immobilization under Dutch conditions will be discussed. The first article deals with the available equipment for remote anaesthesia, their indications for use and some basic darting principles. Part two discusses the various anaesthetics used in wild animal immobilization and their clinical pharmacological properties. A table with effective anaesthetic combinations for ten different species is presented. The third article discusses safety measures and complications which can occur when dealing with wild animal anaesthesia.