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Cognitive outcome in urea cycle disorders.

Despite treatment, cognitive and motor deficits are common in individuals with inherited urea cycle disorders. However, the extent to which the deficits involve specific cognitive or sensorimotor domains is unknown. Furthermore, little is known about the neurochemical basis of cognitive impairment in these disorders. This paper reviews studies of cognitive and motor dysfunction in urea cycle disorders, and discusses potential venues for investigation of the underlying neural basis that may elucidate these defects. Such methods of investigation may serve as a model for studying the relationship between genes, biochemical markers, brain function, and behavior in other metabolic diseases.

Age of Onset↗

MPTP potentiates 3-nitropropionic acid-induced striatal damage in mice: reference to striatonigral degeneration.

Striatonigral degeneration (SND) is a parkinsonian disorder due to the combined degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and striatal output neurons. The aims of this study were to explore (1) the behavioral and histopathological consequences of combined MPTP plus 3-nitropropionic acid (3-NP) intoxication in C57/Bl6 mice and (2) its ability to reproduce the neuropathological hallmarks of SND. 3-NP was administered i.p. every 12 h (total dose=450 mg/kg in 9 days) and MPTP i.p. at 10 mg/(kg day) (total dose=90 mg/kg in 9 days). Four groups of mice (n=10) were compared: control, 3-NP alone, MPTP alone, MPTP + 3-NP. Mice intoxicated with 3-NP and MPTP + 3-NP developed motor symptoms, including hindlimb dystonia and clasping, truncal dystonia and impaired balance adjustments. The severity of motor disorder was worse and lasted longer in MPTP + 3-NP-treated mice compared to 3-NP alone, MPTP alone and controls. 3-NP and MPTP + 3-NP-treated mice also displayed altered gait patterns, impaired motor performance on the pole test, rotarod and traversing a beam tasks and activity parameters. Several of these sensorimotor deficits were also more severe and lasted longer in MPTP + 3-NP-treated mice. Histology demonstrated increased neuronal loss along with astrocytic activation (glial fibrillary acid protein, GFAP) and a higher incidence of circumscribed striatal lateral lesions in MPTP + 3-NP-treated mice compared to 3-NP. Neuronal loss and astrocytic activation were increased in the lateral part of the striatum in 3-NP-intoxicated mice while observed both in the medial and lateral part in MPTP + 3-NP-intoxicated mice. There was also a significant loss of SNc dopaminergic neurons and striatal terminals, similar to that in MPTP-treated mice. Altogether, these results suggest that MPTP potentiates striatal damage and behavioral impairments induced by 3-NP intoxication in mice and constitutes a useful model of the motor disorder and its histopathological correlates in SND.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

Medullary reticular formation activity during ingestion and rejection in the awake rat.

The consummatory components of ingestion and rejection, organized in the caudal brainstem, include licking, swallowing, and the oral phase of rejection (gaping). Studies employing electrical-stimulation induced motor activity have localized interneurons controlling these complex motor patterns to the medullary reticular formation (RF), but the characteristics of these neurons during more naturally induced behavior are unknown. The purpose of the present study was to record the activity profiles of RF neurons during licking, swallowing, and oral rejection in response to gustatory stimulation. Two-hundred and two neurons recorded from awake, freely moving rats were broadly classified as orally related (67%) or non-orally related (33%). Orally related neurons included a large number that were rhythmically active during licking (n = 76; 38%). These "lick-rhythmic" neurons were widely distributed in the RF, but were concentrated in the caudal medullary reticular formation adjacent to the hypoglossal nucleus (Probst's region) and further rostral in the intermediate zone (IRt) of the RF. An analysis of autocorrelations determined that lick-rhythmic neurons in these regions were more closely coupled to licking than to lick-rhythmic neurons more lateral in the parvocellular RF (PCRt). In addition to neurons with weak lick-rhythmic activity, the PCRt also contained a disproportionate number of neurons with orosensory or mixed oro-sensorimotor properties. These data provide evidence for functional specialization within different regions of the medullary RF. A high proportion of lick-rhythmic neurons also showed differential activity associated with swallowing (41%) and/or gaping (75%), further suggesting that the different components of ingestion and rejection share brainstem substrates instead of being produced by unique subsets of interneurons.

Action Potentials↗

Early spatial memory deficit induced by 2,5-hexanedione in the rat.

2,5-Hexanedione (2,5-HD), the major common neurotoxic metabolite of n-hexane and methyl n-butyl ketone, causes a delayed neuropathy with associated sensorimotor impairments. The question arises as to whether specific cognitive deficits occur even prior to changes in sensorimotor ability. The present experiments examined the effects of 2,5-HD on spatial navigation of rats in a water maze at levels/times that did not affect spontaneous exploratory motor activity in an open field holeboard apparatus. Exposure to 1% 2,5-HD in the drinking water for 2 weeks did not significantly affect escape learning, as measured by latency to find a hidden platform. However, 2,5-HD treated animals were impaired in the use of a spatial strategy during a recall test. A similar impairment in spatial memory was observed after i.p. injection of 500 mg/kg/day 2,5-HD for 4 days, in the absence of significant changes in sensorimotor ability or weight loss. Thus 2,5-HD may mediate some of the cognitive effects of hexacarbons and these changes can occur prior to the development of motor symptoms.

Animals↗

The etiology, assessment, and treatment of fecal incontinence.

Fecal incontinence is a common symptom that often impairs quality of life. It is generally caused by a variety of conditions that are associated with anorectal sensorimotor dysfunction and/or diarrhea. Assessment should be tailored to age and symptom severity. Modulation of disordered bowel habits is the key to management; biofeedback and surgery might also be beneficial.

Antidiarrheals↗

MK-801 neurotoxicity in male mice: histologic effects and chronic impairment in spatial learning.

Several histological and behavioral experiments were conducted to investigate the neurotoxic effects of MK-801 in male mice. Moderate subcutaneous (s.c.) doses of MK-801 (0.5 and 1.0 mg/kg) induced the formation of intracytoplasmic vacuoles in pyramidal neurons in layers III and IV of the posterior cingulate/retrosplenial (PC/RS) cortex in 50% and 100% of the mice from the two respective treatment groups. Electron microscopic analysis of the vacuoles indicated that mitochondria and endoplasmic reticulum are the cellular organelles most prominently involved in this pathomorphological change. Treating mice with a high systemic dose of MK-801 (10 mg/kg s.c. or intraperitoneal (i.p.)) caused selective, irreversible degeneration of a small number of PC/RS cortical neurons. Compared to saline controls, the acquisition performance of mice treated i.p. with 10 mg/kg MK-801 was chronically impaired on a spatial learning task (modified hole board food search task) when tested at several posttreatment intervals (up to at least 5 months), although the groups did not differ on activity or sensorimotor tests conducted 2 weeks posttreatment. In summary, MK-801 caused histopathological changes in the mouse brain similar to those observed in the rat. Furthermore, high dose MK-801 treatment that killed a small number of mouse PC/RS cortical neurons resulted in a chronic acquisition impairment in spatial learning, an effect not previously demonstrated in any species.

Animals↗

Response of serotonin-containing neurons in nucleus raphe magnus to morphine, noxious stimuli, and periaqueductal gray stimulation in freely moving cats.

Extracellular single-unit recordings were made in nucleus raphe magnus in unanesthetized, unrestrained cats. Discharge of serotonergic neurons in this region was increased when animals were aroused by noxious stimuli such as pinch and radiant heating of the tail, but these cells were not specifically nociceptive. Peristimulus time histograms indicated that stimulation in the periaqueductal gray was excitatory but alveolar nerve stimulation at a noxious current intensity was no more effective than nonnoxious nerve stimulation in activating serotonergic unit discharge: Similarly, stressful treatments such as physical restraint increased the discharge of some serotonergic neurons, but these cells were activated during any period of behavioral arousal whether or not arousal was the result of aversive treatment. Injection of Formalin into the paw produced pain lasting about 30 min without increasing serotonergic unit discharge above rates observed during undisturbed active waking behavior. The activity of serotonergic neurons was not increased by an analgesic dose of morphine (2 mg/kg, i.p.). These results then are not consistent with the hypothesis that morphine analgesia depends on activation of serotonergic neurons in nucleus raphe magnus or that these cells are specifically involved in modulation of nociception. These neurons may, however, be involved in nociceptive control within the context of a general modulation of sensorimotor processes by serotonin in the central nervous system. We did observe neurochemically unidentified neurons in the medulla whose discharge was more specifically activated by aversive stimuli and also by morphine. It is possible that these neurons are more directly involved in the mediation of opiate and/or stress-induced analgesia.

Analgesia↗

Oscillatory activity reflects the excitability of the human somatosensory system.

The neuronal activity of the resting human brain is dominated by spontaneous oscillations in primary sensory and motor areas. These oscillations are thought to reflect the excitability of sensory and motor systems that can be modulated according to the actual behavioral demands. However, so far, evidence for an association between oscillatory activity and excitability has been inconsistent. Here, we used magnetoencephalography to reinvestigate the relationship between oscillatory activity and excitability in the somatosensory system on a single trial basis. Brief painful stimuli were applied to relate pain-induced suppressions of oscillatory activity to pain-induced increases in excitability. The analysis reveals a significant negative correlation between sensorimotor oscillatory activity, particularly in the alpha-band, and excitability of somatosensory cortices. Oscillatory activity outside the somatosensory system did not correlate with somatosensory excitability. These findings demonstrate that modulations of sensorimotor oscillatory activity specifically reflect modulations in excitability of the somatosensory system and thus provide direct evidence for the basic tenet of an association between oscillatory activity and cortical excitability.

Adult↗

The Wisconsin Card Sorting Test: theoretical analysis and modeling in a neuronal network.

Neuropsychologists commonly use the Wisconsin Card Sorting Test as a test of the integrity of frontal lobe functions. However, an account of its range of validity and of the neuronal mechanisms involved is lacking. We analyze the test at 3 different levels. First, the different versions of the test are described, and the results obtained with normal subjects and brain-lesioned patients are reviewed. Second, a computational analysis is used to reveal what algorithms may pass the test, and to predict their respective performances. At this stage, 3 cognitive components are isolated that may critically contribute to performance: the ability to change the current rule when negative reward occurs, the capacity to memorize previously tested rules in order to avoid testing them twice, and the possibility of rejecting some rules a priori by reasoning. Third, a model neuronal network embodying these 3 components is described. The coding units are clusters of neurons organized in layers, or assemblies. A sensorimotor loop enables the network to sort the input cards according to several criteria (color, form, etc.). A higher-level assembly of rule-coding clusters codes for the currently tested rule, which shifts when negative reward is received. Internal testing of the possible rules, analogous to a reasoning process, also occurs, by means of an endogenous auto-evaluation loop. When lesioned, the model reproduces the behavior of frontal lobe patients. Plausible biological or molecular implementations are presented for several of its components.

Frontal Lobe↗

Active sensation: insights from the rodent vibrissa sensorimotor system.

Rats sweep their vibrissae through space to locate objects in their immediate environment. In essence, their view of the proximal world is generated through pliable hairs that tap and palpate objects. The texture and shape of those objects must be discerned for the rat to assess the value of the object. Furthermore, the location of those objects must be specified with reference to the position of the rat's head for the rat to plan its movements. Recent in vivo and in vitro electrophysiological measurements provide insight into the algorithms and mechanisms that underlie these behavioral-based computations.

Action Potentials↗

Correlations between task-related activity and responses to perturbation in primate sensorimotor cortex.

1. Monkeys were trained to maintain hand position against a range of constant forces. Short-latency responses to passive wrist extension or flexion, as well as short-latency responses to stretch of a single wrist muscle, were recorded from units in areas 4, 3, 1, and 2. These responses were compared to unit activity during active holding and during active movement. 2. Units related to active holding and to active movement were most common in areas 4 and 2. Three-quarters of these units displayed a specific correlation between their passive and active behaviors. Thus, a unit excited by passive extension was excited during active holding against extension force and excited during an active flexion movement. This behavior is similar to the expected concurrent behavior of muscle stretch receptors. By demonstrating that a significant number of task-related units give qualitatively similar responses to passive extension and passive flexion, the results appear to explain the disagreement among previous studies (5, 9, 36) in regard to area 4 behavior during active and passive movements. 3. Area 4 units responded similarly to passive wrist extension and electromagnetic stretch of a single flexor muscle occurring in the absence of wrist extension, indicating that muscle stretch was important in determining area 4 unit responses to passive movements. 4. The similarity of area 4 behavior to area 2 behavior in active and passive situations, along with the observation that area 2 responses to passive movements occurred several milliseconds earlier than those of area 4, emphasizes the importance of area 2 in motor performance and is consistent with significant area 2 mediation of area 4 responses. 5. Results support the hypothesis of an oligosynaptic transcortical pathway (22, 32, 34), beginning in large part with muscle stretch receptors. Furthermore, the correlation noted between short-latency responses to passive movement and task-related activity suggests that this transcortical pathway not only mediates responses to passive movement but may be responsible, to a significant degree, for task-related activity during undisturbed performance. Thus, active position maintenance and active movement were probably accomplished, at least in part, by increasing and decreasing the influence of this pathway on specific area 4 neurons and thereby producing the patterns of area 4 activity responsible for task performance.

Animals↗

GABAergic neurons in mammalian thalamus: a marker of thalamic complexity?

The present study evaluated the occurrence, distribution, and number of GABAergic neurons in the thalamus of different mammalian species (bat, mouse, rat, guinea pig, rabbit, cat, monkey, humans), by means of light microscopical immunoenzymatic localization of GABA or of its biosynthetic enzyme glutamic acid decarboxylase and by ultrastructural immunogold detection of GABA. Our data demonstrated that: 1) GABAergic local circuit neurons were detected in the thalamic visual domain in all the species analyzed, whereas in other thalamic nuclei their presence and number varied among species; 2) the number of GABAergic local circuit neurons progressively increased in the dorsal thalamus of species with more complex behavior; 3) the presence of local circuit neurons conferred a similar intrinsic organization to the dorsal thalamic nuclei, characterized by complex synaptic arrangements; 4) in the reticular thalamic nucleus, whose neurons were GABA-immunoreactive in all the examined species, the cellular density decreased from the bat to humans. These findings strongly suggest that thalamic GABAergic local circuit neurons are not directly related to the ability to perform specific sensorimotor tasks, but they are likely to reflect an increasing complexity of the local information processing that occurs at thalamic level.

Animals↗

[Characteristics of heterochromatin of heterophase nuclei from interphase neurons of various brain structures selected for the nervous system excitability].

Quantitative characteristics (the area and number of chromocenters) of the interphase C-heterochromatin in the nuclei of pyramidal neurons of the midbrain reticular formation, sensorimotor cortex, and hippocampus (CA3) of rat strains with different genetically determined excitability were studied in the normal state of the animals and after exposure to a short-term emotional pain stress. The results indicate a relationship between the excitability of the nervous system and structural-functional state of the neuronal interphase heterochromatin. The role of cytogenetic features of different brain structures in the CNS functioning and behavior and their relation with genetically determined excitability of the nervous system are discussed.

Animals↗

Analysis of theta power in hippocampal EEG during bar pressing and running behavior in rats during distinct behavioral contexts.

These experiments examine changes in theta power as measured by wavelet analysis in five rats performing a conditional visual discrimination task and a simple running task. In the conditional task, rats were trained to press one lever to initiate a trial and then to press one of two choice levers, each corresponding to one of two cue lights. Analysis of theta power in this operant task found a large decrease in theta power during the choice bar presses, in contrast to the increase in theta power during trial initiation bar presses. This result seems to stand counter to results that propose consistent relationships between motor actions and theta power (Vanderwolf, EEG Clin Neurophys 26:407-418, 1969), as well as studies suggesting that the lack of bar-press theta is the result of habituation. However, these data can be seen as being in broad agreement with the theoretical framework of sensorimotor integration (Bland and Oddie, Behav Brain Res 127:119-136, 2001). To investigate further the power of theta observed at the termination of type 1 motor activity, a runway task was devised in which rats ran back and forth between two ends of a linear track, one of which was always rewarded and the other never rewarded. Theta power decreased sharply 240 ms before movement ended at the rewarded end, but not at the unrewarded end of the track. These data extend the current scope of theory in demonstrating that hippocampal theta activity can end abruptly 200-400 ms prior to the end of type 1 motor movement when approaching the end of a motor sequence.

Action Potentials↗

[Neuronal plasticity exemplified by the somatosensory system].

The mammalian brain is capable of a substantial functional reorganization, manifesting on a cortical somatotopical and on a behavioral level. Possible mechanisms are reviewed based on the work by others and ourselves on somatosensory reorganization in humans. The somatosensory system is characterized by divergent projections from the periphery to the cerebral cortex. Changes in synaptic weights allow for reorganization of sensory processing: On one side, limb amputation will result in a representational "invasion" of the differentiated cortex from neighboring regions with concomitant perceptual changes. On the other side, sensorimotor training can increase the representational cortical zone of a limb. Plastic changes can be temporary or persistent. Modulating factors like pain and certain drugs seem to induce a permissive state in the cortex resulting in enhanced reorganization. Thus, specific physical training combined with pharmacoceutical modulation holds promise to improve functional recovery after brain lesions.

Afferent Pathways↗

Excitatory postsynaptic potentials recorded from regular-spiking cells in layers II/III of rat sensorimotor cortex.

1. Intracellular recording techniques were used to investigate the physiological and pharmacological properties of stimulus-induced excitatory postsynaptic potentials (EPSPs) recorded in regular-spiking cells located in layers II/III of rat sensorimotor cortical slices maintained in vitro. 2. Depending on the strength of the extracellular stimuli, a pure EPSP or an EPSP-inhibitory postsynaptic potential sequence was observed under perfusion with normal medium. The EPSPs displayed short latency of onset [2.4 +/- 0.7 (SD) ms] and were able to follow repetitive stimulation (tested less than or equal to 5 Hz). Variation of the membrane potential (Vm) revealed two types of voltage behavior for the short-latency EPSP. The first type decreased in amplitude with depolarization and increased in amplitude with hyperpolarization. In contrast, the second type behaved anomalously by increasing and decreasing in size after depolarization and hyperpolarization, respectively. 3. Several experimental procedures were carried out to investigate the mechanism underlying the anomalous voltage behavior of the EPSP. Results indicated that this type of Vm dependency could be mimicked by an intrinsic response evoked by a brief pulse of depolarizing current and could be abolished by N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium bromide (50 mM). Furthermore, the EPSP was not sensitive to the N-methyl-D-aspartate (NMDA) receptor antagonist 3-((+-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP, 10 microM). Thus the anomalous voltage relationship of the neuronal membrane. 4. The involvement of non-NMDA receptors in excitatory synaptic transmission was investigated with their selective antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 1-10 microM). This drug greatly reduced or completely blocked the EPSP in a dose-dependent manner (1-10 microM). The IC50 for the CNQX effect was approximately 2 microM. In the presence of CNQX (10 microM) and glycine (10 microM), synaptic stimulation failed to elicit firing of action potential. However, a CPP-sensitive EPSP was observed. 5. When synaptic inhibition was reduced by low concentration of bicuculline methiodide (BMI, 1-2 microM), extracellular stimulation revealed late EPSPs (latency to onset: 10-30 ms) that were not discernible in normal medium. Similar to the short-latency EPSP, the Vm dependency displayed by this late EPSP could be modified by inward membrane rectifications. The late EPSP appeared to be polysynaptic in origin because 1) its latency of onset was long and variable and 2) it failed to follow repetitive stimuli delivered at a frequency that did not depress the short-latency EPSP.(ABSTRACT TRUNCATED AT 400 WORDS)

6-Cyano-7-nitroquinoxaline-2,3-dione↗

Brainstem control of orienting movements: intrinsic coordinate systems and underlying circuitry.

A fundamental issue in the understanding of how the nervous system processes information is the way in which sensory information is used to initiate and guide movements. Recent progress has been made by taking an information processing approach in which information--for example, the spatial location of an object towards which an animal will orient--is tracked through the nervous system from sensory to motor levels. In this approach, neurally encoded information is characterized in terms of its representation within a neural or intrinsic coordinate system or set of neural coding parameters. For example, the retina codes spatial location in terms of the location of activity on the retinal surface, whereas motoneurons code spatial location in terms of the pulling directions of the muscles they activate. In between these two peripheral stages, the information passes through intermediate coordinate systems. These intermediate coordinate systems can be characterized by recording or altering the activity of small groups of neurons while an animal is performing a well-defined sensorimotor task. Spatial location information is used to guide orienting movements, those movements made by the eyes, ears, head, or body which function to center an object of interest in the animal's visual field. The optic tectum and forebrain, their connections to the medial mesencephalic and rhombencephalic brainstem tegmental cell groups, and subsequent connections to brainstem motor nuclei and spinal cord are employed to control fundamental aspects of this behavior. Studies reviewed herein indicate that following the retinotopic coding of spatial location in the retina and tectum, spatial location information appears to enter a different coordinate system at tegmental levels in which spatial aspects of orienting movement are coded in terms of their discrete horizontal and vertical components. This Cartesian coordinate system is an example of an abstract neural coordinate system, in that it is a simple, low-dimensional representation of spatial location which differs greatly from both sensory and motor representations. Also, this Cartesian representation may be common to many orienting movements, yet it appears to differ from the coordinate systems controlling other movement types such as stabilization or phasic movements. This suggests an hypothesis in which coordinate systems, especially at intermediate levels of processing, may be organized according to behavioral task as opposed to being determined by the particular sensory or motor system involved in the behavior. Understanding the evolutionary heritage and computational function of abstract neural coordinate systems, and the relation between different coordinate systems and behavioral tasks may be useful in understanding general aspects of sensory information processing and motor control.

Animals↗

Methylphenidate modulates cerebral post-stroke reorganization.

OBJECTIVE: We hypothesized that a single dose of methylphenidate (MP) would modulate cerebral motor activation and behavior in patients having suffered a subcortical stroke. METHODS: Eight men with a single stroke on the corticospinal tract resulting in a pure motor hemiparesia were included in a randomized, cross-over, double-blind, placebo-controlled study. Patients were first evaluated 17 days after stroke onset by validated neurological scales, motor tests and fMRI (flexion/extension of the digits) after 20 mg MP or placebo. Seven days later, the patients underwent the same protocol and received the drug they had not taken at the first evaluation. Each patient was his own control. RESULTS: Placebo intake did not change performance. MP compared to placebo elicited a significant improvement in motor performance of the affected hand at the finger tapping test. MP induced: (1) a hyperactivation of the ipsilesional primary sensorimotor cortex including the motor hand and face areas and of the contralesional premotor cortex; (2) a hypoactivation of the ipsilesional anterior cingulum. Hyperactivation in the face motor area correlated positively with the improvement in performance. CONCLUSION: We demonstrated that the reorganized network may efficiently be targeted by the drug and that the effect of MP might partly rely on an improvement in attention/effort through cingulum modulation.

Aged↗