Classifying Disorders of Consciousness: Past, Present, and Future.

With the advent of advanced analytical methods applied to functional neuroimaging and neurophysiological data, cerebral conditions have been defined that challenge the established classification of disorders of consciousness. A subset of brain-damaged patients has been identified who cannot carry out motor commands, but who exhibit patterns of cerebral activation during mental imagery tasks that are indistinguishable from those in healthy controls. This condition, termed "cognitive motor dissociation," has overturned many assumptions regarding the detection, diagnosis, prognosis, and care of patients with brain injury. Three factors are likely to influence efforts to improve the classification of disorders of consciousness in the near future: the types of data that will become available to characterize brain states, the modeling paradigms utilized for data analysis, and the ability to implement classification schemes in the clinical setting. Here we review past achievements, present states, and future projections for the classification of impaired consciousness and responsiveness.

The significance of anti-neuronal antibodies for acute psychiatric disorders: a retrospective case-controlled study.

BACKGROUND: The clinical significance of anti-neuronal antibodies in patients with psychiatric disorders, but without encephalitis, remains unknown. In patients admitted to acute psychiatric inpatient care we aimed to identify clinical features distinguishing anti-neuronal antibody positive patients from matched controls. RESULTS: Patients who were serum-positive to N-methyl D-aspartate receptor (NMDAR) (n = 21), contactin-associated protein 2 (CASPR2) (n = 14) and/or glutamic acid decarboxylase 65 (GAD65) (n = 9) antibodies (cases) were age and sex matched (1:2) with serum-negative patients from the same cohort (controls). The prevalence and severity of psychiatric symptoms frequently encountered in NMDAR, CASPR2 and GAD65 antibody associated disorders were compared in cases and controls. NMDAR, CASPR2 and GAD65 antibody positive patients did not differ in their clinical presentation from matched serum negative controls. CONCLUSION: In this cohort, patients with and without NMDAR, CASPR2 and GAD65 antibodies admitted to acute psychiatric inpatient care had similar psychiatric phenotypes. This does not exclude their clinical relevance in subgroups of patients, and studies further investigating the clinical significance of anti-neuronal antibodies in patients with psychiatric symptomatology are needed.

[Workup and treatment of autoimmune encephalitis]. / Udredning og behandling afautoimmun encephalitis.

Autoimmune encephalitis with antibodies against neuronal surface antigens is diagnosed with increasing frequency in recent years. If treated early and aggressively, these conditions often respond favourably to immunotherapy. We describe the clinical features, diagnosis and treatment of the two most common types of autoimmune encephalitis with antibodies against the N-methyl-D-aspartate receptor or the leucine-rich glioma-inactivated 1 protein. Together, these two conditions comprise 80% of the autoimmune encephalitis cases diagnosed in Denmark. Autoimmune encephalitides with rare antibodies are also summarized.

Altered 13C glucose metabolism in the cortico-striato-thalamo-cortical loop in the MK-801 rat model of schizophrenia.

Using a modified MK-801 (dizocilpine) N-methyl-D-aspartic acid (NMDA) receptor hypofunction model for schizophrenia, we analyzed glycolysis, as well as glutamatergic, GABAergic, and monoaminergic neurotransmitter synthesis and degradation. Rats received an injection of MK-801 daily for 6 days and on day 6, they also received an injection of [1-(13)C]glucose. Extracts of frontal cortex (FCX), parietal and temporal cortex (PTCX), thalamus, striatum, nucleus accumbens (NAc), and hippocampus were analyzed using (13)C nuclear magnetic resonance spectroscopy, high-performance liquid chromatography, and gas chromatography-mass spectrometry. A pronounced reduction in glycolysis was found only in PTCX, in which (13)C labeling of glucose, lactate, and alanine was decreased. (13)C enrichment in lactate, however, was reduced in all areas investigated. The largest reductions in glutamate labeling were detected in FCX and PTCX, whereas in hippocampus, striatum, and Nac, (13)C labeling of glutamate was only slightly but significantly reduced. The thalamus was the only region with unaffected glutamate labeling. γ-Aminobutyric acid (GABA) labeling was reduced in all areas, but most significantly in FCX. Glutamine and aspartate labeling was unchanged. Mitochondrial metabolites were also affected. Fumarate labeling was reduced in FCX and thalamus, whereas malate labeling was reduced in FCX, PTCX, striatum, and NAc. Dopamine turnover was decreased in FCX and thalamus, whereas that of serotonin was unchanged in all regions. In conclusion, neurotransmitter metabolism in the cortico-striato-thalamo-cortical loop is severely impaired in the MK-801 (dizocilpine) NMDA receptor hypofunction animal model for schizophrenia.

1H MR spectroscopy of gray and white matter in carbon monoxide poisoning.

Carbon monoxide (CO) intoxication leads to acute and chronic neurological deficits, but little is known about the specific noxious mechanisms. (1)H magnetic resonance spectroscopy (MRS) may allow insight into the pathophysiology of CO poisoning by monitoring neurochemical disturbances, yet only limited information is available to date on the use of this protocol in determining the neurological effects of CO poisoning. To further examine the short-term and long-term effects of CO on the central nervous system, we have studied seven patients with CO poisoning assessed by gray and white matter MRS, magnetic resonance imaging (MRI) and neuropsychological testing. Five patients suffered from acute high-dose CO intoxication and were in coma for 1-6 days. In these patients, MRI revealed hyperintensities of the white matter and globus pallidus and also showed increased choline (Cho) and decreased N-acetyl aspartate (NAA) ratios to creatine (Cr), predominantly in the white matter. Lactate peaks were detected in two patients during the early phase of high-dose CO poisoning. Two patients with chronic low-dose CO exposure and without loss of consciousness had normal MRI and MRS scans. On follow-up. five of our seven patients had long-lasting intellectual impairment, including one individual with low-dose CO exposure. The MRS results showed persisting biochemical alterations despite the MRI scan showing normalization of morphological changes. In conclusion, the MRS was normal in patients suffering from chronic low-dose CO exposure; in contrast, patients with high-dose exposure showed abnormal gray and white matter levels of NAA/Cr, Cho/Cr and lactate, as detected by (1)H MRS, suggesting disturbances of neuronal function, membrane metabolism and anaerobic energy metabolism, respectively. Early increases in Cho/Cr and decreases of NAA/Cr may be related to a poor long-term outcome, but confirmation by future studies is needed.

Repeated injection of MK801: an animal model of schizophrenia?

Glutamate-induced neurotoxicity plays an important role in neurological and psychiatric diseases. Thus, much attention has been given to the potential neuroprotective role of glutamate receptor antagonists, especially to those acting on the N-methyl-d-aspartate (NMDA) subtype. However, in addition to their neuroprotective potential, these compounds have also neurotoxic and psychotogenic properties. In the present study we used repeated injections of MK801 to examine if this non-competitive NMDA receptor antagonist could be used to produce schizophrenia-like alterations in behavior and brain metabolism in animals. Rats were given injections of MK801 (0.1 mg/kg) on six consecutive days, the last dose together with [1-(13)C]glucose and [1,2-(13)C]acetate, to probe neuronal and astrocytic metabolism, respectively. Analyses of extracts from parts of the frontal cortex plus cingulate and retrosplenial cortices and temporal lobes were performed using (13)C and (1)H magnetic resonance spectroscopy. Changes in glutamate and glutamine were restricted to the temporal lobe, in which amounts and labeling from [1-(13)C]glucose and [1,2-(13)C]acetate were increased compared to control. Locomotor activity was slightly higher in rats treated with MK801 compared to untreated animals. Metabolic changes did not resemble the alterations occurring in schizophrenia and those after repeated high dose (0.5 mg/kg) [Kondziella, D., Brenner, E., Eyjolfsson, E.M., Markinhuhta, K.R., Carlsson, M., Sonnewald, U., 2005. Glial-neuronal interactions are impaired in the schizophrenia model of repeated MK801 exposure. Neuropsychopharmacology, Epub ahead of print] but rather those caused by MK801 seen after a single high dose (0.5 mg/kg) [Brenner, E., Kondziella, D., Haberg, A., Sonnewald, U., 2005. Impaired glutamine metabolism in NMDA receptor hypofunction induced by MK801. J. Neurochem. 94, 1594-1603.].

Impaired glutamine metabolism in NMDA receptor hypofunction induced by MK801.

Paradoxically, glutamate receptor antagonists have neurotoxic and psychotogenic properties in addition to their neuroprotective potential during excessive glutamate release. In the present study the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK801 was used to examine glial-neuronal interactions in NMDA receptor hypofunction. Rats were given a subanesthetic dose of MK801 together with [1-13C]glucose and [1,2-13C]acetate, and brains were removed 20 min later. Analyses of extracts from cingulate, retrosplenial plus middle frontal cortices (CRFC) and temporal lobe were performed using HPLC and 13C and 1H nuclear magnetic resonance spectroscopy. Hypofunction of the NMDA receptor induced similar changes in both brain areas investigated; however, the changes were most pronounced in the temporal lobe. Generally, only labeling from [1-13C]glucose was affected by MK801. In CRFC and temporal lobe amounts of both labeled and unlabeled glutamine were increased, whereas those of aspartate were decreased. In the CRFC the decrease in labeling of aspartate was greater than the decrease in concentration, leading to decreased 13C enrichment. In temporal lobe, not in CRFC, increased concentrations of glutamate, GABA, succinate, glutathione and inositol were detected together with increased labeling of GABA and succinate from [1-13C]glucose. 13C Enrichment was decreased in glutamate and increased in succinate. The results point towards a disturbance in glutamate-glutamine cycling and thus interaction between neurons and glia, since labeling of glutamate and glutamine from glucose was affected differently.