Abnormal Drug Metabolism after Barbiturate and Paracetamol Overdose

Drug-metabolizing capacity has been assessed by serial measurements of the plasma antipyrine half life in 11 patients with severe barbiturate intoxication and in 17 patients with acute hepatic necrosis due to paracetamol overdosage. Drug metabolism was strikingly enhanced after barbiturate over-dosage, and this effect was still present six weeks later. In contrast the antipyrine half life was greatly prolonged in patients with paracetamol-induced acute hepatic necrosis but returned to normal or near-normal values within seven to 21 days.     

Radial Glial Fibers Promote Neuronal Migration and Functional Recovery after Neonatal Brain Injury

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CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury

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MRI of Neuronal Recovery after Low-Dose Methamphetamine Treatment of Traumatic Brain Injury in Rats

We assessed the effects of low dose methamphetamine treatment of traumatic brain injury (TBI) in rats by employing MRI, immunohistology, and neurological functional tests. Young male Wistar rats were subjected to TBI using the controlled cortical impact model. The treated rats (n = 10) received an intravenous (iv) bolus dose of 0.42 mg/kg of methamphetamine at eight hours after the TBI followed by continuous iv infusion for 24 hrs. The control rats (n = 10) received the same volume of saline using the same protocol. MRI scans, including T2-weighted imaging (T2WI) and diffusion tensor imaging (DTI), were performed one day prior to TBI, and at 1 and 3 days post TBI, and then weekly for 6 weeks. The lesion volumes of TBI damaged cerebral tissue were demarcated by elevated values in T₂ maps and were histologically identified by hematoxylin and eosin (H&E) staining. The fractional anisotropy (FA) values within regions-of-interest (ROI) were measured in FA maps deduced from DTI, and were directly compared with Bielschowsky’s silver and Luxol fast blue (BLFB) immunohistological staining. No therapeutic effect on lesion volumes was detected during 6 weeks after TBI. However, treatment significantly increased FA values in the recovery ROI compared with the control group at 5 and 6 weeks after TBI. Myelinated axons histologically measured using BLFB were significantly increased (p<0.001) in the treated group (25.84±1.41%) compared with the control group (17.05±2.95%). Significant correlations were detected between FA and BLFB measures in the recovery ROI (R = 0.54, p<0.02). Methamphetamine treatment significantly reduced modified neurological severity scores from 2 to 6 weeks (p<0.05) and foot-fault errors from 3 days to 6 weeks (p<0.05) after TBI. Thus, the FA data suggest that methamphetamine treatment improves white matter reorganization from 5 to 6 weeks after TBI in rats compared with saline treatment, which may contribute to the observed functional recovery.     

Depletion of Brain Docosahexaenoic Acid Impairs Recovery from Traumatic Brain Injury

Omega-3 fatty acids are crucial for proper development and function of the brain where docosahexaenoic acid (DHA), the primary omega-3 fatty acid in the brain, is retained avidly by the neuronal membranes. We investigated the effect of DHA depletion in the brain on the outcome of traumatic brain injury (TBI). Pregnant mice were put on an omega-3 fatty acid adequate or deficient diet from gestation day 14 and the pups were raised on the respective diets. Continuation of this dietary regime for three generations resulted in approximately 70% loss of DHA in the brain. Controlled cortical impact was delivered to both groups of mice to produce severe TBI and the functional recovery was compared. Compared to the omega-3 adequate mice, the DHA depleted mice exhibited significantly slower recovery from motor deficits evaluated by the rotarod and the beam walk tests. Furthermore, the DHA deficient mice showed greater anxiety-like behavior tested in the open field test as well as cognitive deficits evaluated by the novel object recognition test. The level of alpha spectrin II breakdown products, the markers of TBI, was significantly elevated in the deficient mouse cortices, indicating that the injury is greater in the deficient brains. This observation was further supported by the reduction of NeuN positive cells around the site of injury in the deficient mice, indicating exacerbated neuronal death after injury. These results suggest an important influence of the brain DHA status on TBI outcome.     

Mental Processes and the Brain During Dreams.

This article examines the different theoretical approaches to dreaming and compares them with recent data from brain-mapping studies. Two lines of investigation were considered: a neurobiological and a cognitive approach. Both lines of investigation can be usefully integrated into recent research using the techniques of brain mapping. Two aspects of particular interest are discussed: (a) The pattern of limbic and paralimbic activation in rapid eye movement (REM) and non-REM could explain some differences of oneiric hallucination during different stages of sleep, and (b) the deactivation of the heteromodal cortex could explain the loss of reality testing and the absence of self-consciousness during dreams. The complex nature of the dreaming phenomenon makes it necessary to distinguish clearly between mental representation and the underlying neurobiological changes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Glutamate and Brain Glutaminases in Drug Addiction

Glutamate is the principal excitatory neurotransmitter in the central nervous system and its actions are related to the behavioral effects of psychostimulant drugs. In the last two decades, basic neuroscience research and preclinical studies with animal models are suggesting a critical role for glutamate transmission in drug reward, reinforcement, and relapse. Although most of the interest has been centered in post-synaptic glutamate receptors, the presynaptic synthesis of glutamate through brain glutaminases may also contribute to imbalances in glutamate homeostasis, a key feature of the glutamatergic hypothesis of addiction. Glutaminases are the main glutamate-producing enzymes in brain and dysregulation of their function have been associated with neurodegenerative diseases and neurological disorders; however, the possible implication of these enzymes in drug addiction remains largely unknown. This mini-review focuses on brain glutaminase isozymes and their alterations by in vivo exposure to drugs of abuse, which are discussed in the context of the glutamate homeostasis theory of addiction. Recent findings from mouse models have shown that drugs induce changes in the expression profiles of key glutamatergic transmission genes, although the molecular mechanisms that regulate drug-induced neuronal sensitization and behavioral plasticity are not clear.     

Alterations in Spontaneous Brain Oscillations during Stroke Recovery

Amplitude or frequency alterations of spontaneous brain oscillations may reveal pathological phenomena in the brain or predict recovery from brain lesions, but the temporal evolution and the functional significance of these changes is not well known. We performed follow-up recordings of spontaneous brain oscillations with whole-head MEG in 16 patients with first-ever stroke in the middle cerebral artery territory, affecting upper limb motor function, 1–7 days (T₀), 1 month (T₁), and 3 months (T₂) after stroke, with concomitant clinical examination. Clinical test results improved significantly from T₀ to T₁ or T₂. During recovery (at T₁ and T₂), the strength of temporo–parietal ∼10-Hz oscillations in the affected hemisphere (AH) was increased as compared with the unaffected hemisphere. Abnormal low-frequency magnetic activity (ALFMA) at ∼1 Hz in the AH was detected in the perilesional cortex in seven patients at T₀. In four of these, ALFMA persisted at T₂. In patients with ALFMA, the lesion size was significantly larger than in the rest of the patients, and worse clinical outcome was observed in patients with persisting ALFMA. Our results indicate that temporo–parietal ∼10-Hz oscillations are enhanced in the AH during recovery from stroke. Moreover, stroke causes ALFMA, which seems to persist in patients with worse clinical outcome.     

Frequency Band-Specific Electrical Brain Stimulation Modulates Cognitive Control Processes

A large body of findings has tied midfrontal theta-band (4–8 Hz) oscillatory activity to adaptive control mechanisms during response conflict. Thus far, this evidence has been correlational. To evaluate whether theta oscillations are causally involved in conflict processing, we applied transcranial alternating current stimulation (tACS) in the theta band to a midfrontal scalp region, while human subjects performed a spatial response conflict task. Conflict was introduced by incongruency between the location of the target stimulus and the required response hand. As a control condition, we used alpha-band (8–12 Hz) tACS over the same location. The exact stimulation frequencies were determined empirically for each subject based on a pre-stimulation EEG session. Behavioral results showed general conflict effects of slower response times (RT) and lower accuracy for high conflict trials compared to low conflict trials. Importantly, this conflict effect was reduced specifically during theta tACS, which was driven by slower response times on low conflict trials. These results show how theta tACS can modulate adaptive cognitive control processes, which is in accordance with the view of midfrontal theta oscillations as an active mechanism for cognitive control.     

A New Brain Drug Delivery Strategy: Focused Ultrasound-Enhanced Intranasal Drug Delivery

Central nervous system (CNS) diseases are difficult to treat because of the blood-brain barrier (BBB), which prevents most drugs from entering into the brain. Intranasal (IN) administration is a promising approach for drug delivery to the brain, bypassing the BBB; however, its application has been restricted to particularly potent substances and it does not offer localized delivery to specific brain sites. Focused ultrasound (FUS) in combination with microbubbles can deliver drugs to the brain at targeted locations. The present study proposed to combine these two different platform techniques (FUS+IN) for enhancing the delivery efficiency of intranasally administered drugs at a targeted location. After IN administration of 40 kDa fluorescently-labeled dextran as the model drug, FUS targeted at one region within the caudate putamen of mouse brains was applied in the presence of systemically administered microbubbles. To compare with the conventional FUS technique, in which intravenous (IV) drug injection is employed, FUS was also applied after IV injection of the same amount of dextran in another group of mice. Dextran delivery outcomes were evaluated using fluorescence imaging of brain slices. The results showed that FUS+IN enhanced drug delivery within the targeted region compared with that achieved by IN only. Despite the fact that the IN route has limited drug absorption across the nasal mucosa, the delivery efficiency of FUS+IN was not significantly different from that of FUS+IV. As a new drug delivery platform, the FUS+IN technique is potentially useful for treating CNS diseases.     

Ultrasound-Enhanced Drug Transport and Distribution in the Brain

Drug delivery in the brain is limited by slow drug diffusion in the brain tissue. This study tested the hypothesis that ultrasound can safely enhance the permeation of drugs in the brain. In vitro exposure to ultrasound at various frequencies (85 kHz, 174 kHz, and 1 MHz) enhanced the permeation of tritium-labeled molecules with molecular weight up to 70 kDa across porcine brain tissue. A maximum enhancement of 24-fold was observed at 85 kHz and 1,200 J/cm². In vivo exposure to 1-MHz ultrasound further demonstrated the ability of ultrasound to facilitate molecule distribution in the brain of a non-human primate. Finally, ultrasound under conditions similar to those used in vivo was shown to cause no damage to plasmid DNA, siRNA, adeno-associated virus, and fetal rat cortical neurons over a range of conditions. Altogether, these studies demonstrate that ultrasound can increase drug permeation in the brain in vitro and in vivo under conditions that did not cause detectable damage.     

Recovery after prolonged muscular work

Increased protein, tyrosine and 3-methylhistidine content has been observed in the skeletal muscles of rats 2-24 h after a 10-hour swimming period. This was accompanied by a significant rise in 3-methylhistidine excretion during the second day of the recovery period. Such combination of alterations suggests simultaneous augmentation of both protein synthesis and decomposition in the muscles after active work. The start of the alterations coincides with post-exercise increase of blood corticosterone level (2-6 h after work) and with the achievement of glycogen supercompensation in the liver and muscles.     

Recovery after subarachnoid haemorrhage.

OBJECTIVE--To determine the implications of subarachnoid haemorrhage for quality of life and aftercare. DESIGN--Prospective follow up study of patients surviving subarachnoid haemorrhage over one year (at discharge, three months, and one year) by examination of cognitive functions (a test battery) and changes in everyday life (semistructured interview). SETTING--Regional neurosurgical unit at a tertiary referral centre. PATIENTS--100 Patients with subarachnoid haemorrhage; 17 were lost during the study because of ineligibility (further surgery, previous head injury, relevant psychiatric history, and cultural differences), loss of contact, and non-compliance; a further 13 patients who developed a neurological deficit were considered separately. MAIN OUTCOME MEASURE--Performance on cognitive test battery and reported changes in quality of life. RESULTS--At discharge patients with and without neurological deficit scored below established norms with most tests, but by three months the difference had resolved in patients without deficit. Reduced quality of life attributable to subarachnoid haemorrhage at one year mainly included less energy (seven patients), adverse emotional changes (five), early retirement, affected social life, and domestic tension (three each). None reported reduced capacity for work. CONCLUSIONS--Patients surviving subarachnoid haemorrhage without neurological symptoms have a good prognosis and should be encouraged to return to a normal lifestyle within about three months.