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Widespread loss of cerebral connectivity is assumed to underlie the failure of brain mechanisms that support communication and goal-directed behaviour following severe traumatic brain injury. Disorders of consciousness that persist for longer than 12 months after severe traumatic brain injury are generally considered to be immutable; no treatment has been shown to accelerate recovery or improve functional outcome in such cases. Recent studies have shown unexpected preservation of large-scale cerebral networks in patients in the minimally conscious state (MCS), a condition that is characterized by intermittent evidence of awareness of self or the environment. These findings indicate that there might be residual functional capacity in some patients that could be supported by therapeutic interventions. We hypothesize that further recovery in some patients in the MCS is limited by chronic underactivation of potentially recruitable large-scale networks. Here, in a 6-month double-blind alternating crossover study, we show that bilateral deep brain electrical stimulation (DBS) of the central thalamus modulates behavioural responsiveness in a patient who remained in MCS for 6 yr following traumatic brain injury before the intervention. The frequency of specific cognitively mediated behaviours (primary outcome measures) and functional limb control and oral feeding (secondary outcome measures) increased during periods in which DBS was on as compared with periods in which it was off. Logistic regression modelling shows a statistical linkage between the observed functional improvements and recent stimulation history. We interpret the DBS effects as compensating for a loss of arousal regulation that is normally controlled by the frontal lobe in the intact brain. These findings provide evidence that DBS can promote significant late functional recovery from severe traumatic brain injury. Our observations, years after the injury occurred, challenge the existing practice of early treatment discontinuation for patients with only inconsistent interactive behaviours and motivate further research to develop therapeutic interventions.

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BACKGROUND: The minimally conscious state (MCS) resulting from severe brain damage refers to a subset of patients who demonstrate unequivocal, but intermittent, behavioral evidence of awareness of self or their environment. Although clinical examination may suggest residual cognitive function, neurobiological correlates of putative cognition in MCS have not been demonstrated. OBJECTIVE: To test the hypothesis that MCS patients retain active cerebral networks that underlie cognitive function even though command following and communication abilities are inconsistent. METHODS: fMRI was employed to investigate cortical responses to passive language and tactile stimulation in two male adults with severe brain injuries leading to MCS and in seven healthy volunteers. RESULTS: In the case of the patient language-related tasks, auditory stimulation with personalized narratives elicited cortical activity in the superior and middle temporal gyrus. The healthy volunteers imaged during comparable passive language stimulation demonstrated responses similar to the patients' responses. However, when the narratives were presented as a time-reversed signal, and therefore without linguistic content, the MCS patients demonstrated markedly reduced responses as compared with volunteer subjects, suggesting reduced engagement for "linguistically" meaningless stimuli. CONCLUSIONS: The first fMRI maps of cortical activity associated with language processing and tactile stimulation of patients in the minimally conscious state (MCS) are presented. These findings of active cortical networks that serve language functions suggest that some MCS patients may retain widely distributed cortical systems with potential for cognitive and sensory function despite their inability to follow simple instructions or communicate reliably.

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A brief taxonomy of neurologic disorders resulting in global impairments of consciousness is presented. Particular emphasis is placed on focal injuries of subcortical structures that may produce disorders that are otherwise associated to large bilateral cortical injuries. A distinction between subcortical arousal and "gating" systems is developed. Both clinical and experimental studies are reviewed in the context of these disorders and their possible underlying mechanisms.

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We review initial efforts at neuromodulation in the vegetative state and organize several aspects of recent studies of the underlying neurobiology of catastrophic brain injuries. An innovative strategy for patient and target selection for neuromodulation of impaired cognitive function is outlined. Scientific and ethical issues that will attend future efforts to appropriately risk-stratify patients and initiate interventions with therapeutic intent are considered.

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A woman (LR), unconscious for 20 years, spontaneously produces infrequent, isolated words unrelated to any environmental context. Fluorodeoxy-glucose-positron emission tomography (FDG-PET) imaging coregistered with magnetic resonance imaging (MRI) revealed a mean brain metabolism equivalent to deep anesthesia. Nevertheless, PET imaging demonstrated islands of modestly higher metabolism that included Broca's and Wernicke's areas. Functional brain imaging with magnetoencephalographic (MEG) imaging, a technique providing a temporal resolution of better than 1 msec, identified preserved dynamic patterns of spontaneous and evoked brain activity in response to sensory stimulation. Specifically, we examined spontaneous gamma-band activity (near 40 Hz) and its reset or modification during early auditory processing, a measure that correlated with human perception of sensory stimuli (Joliot, Ribary, & Llinás, 1994). Evidence of abnormal and incomplete gamma-band responses appeared in the left hemisphere only in response to auditory or somatosensory stimulation. MEG single-dipole reconstructions localized to the auditory cortex in the left hemisphere and overlapped with metabolically active regions identified by FDG-PET. The observation demonstrates that isolated neuronal groups may express well-defined fragments of activity in a severely damaged, unconscious brain. The motor fixed-action pattern character of her expressed words supports the notion of brain modularity in word generation.

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The clinically described 'persistent vegetative state' (PVS), consists of wakefulness unaccompanied by any evidence of the subject's awareness of self or environment. Past studies from our own and other laboratories have used positron emission tomography (PET) to study brain metabolism in approximately 20 such patients during wakeful periods. All those efforts identified global cerebral glucose metabolism at or below levels encountered during deep barbiturate anaesthesia. Nevertheless, the clinical literature includes rare reports of relatively isolated cognitive functions expressed by PVS patients late in their course. The observation raises the question of whether such activity reflects awareness or unconscious automatic behaviour. We employed magnetometry (MEG), PET scanning, MR imaging and 24-hour EEG recordings to evaluate three patients clinically vegetative between six months and 20 years after onset. Neither meticulous clinical examinations nor 24-hour EEG and video monitoring provided any hint of cognitive interaction in any subject. Nevertheless, patient 1 uttered single words once every 48 hours or more; patient 2 frequently expressed coordinated, non-purposeful, non-dystonic movements in arms and/or legs; and, patient 3 expressed strong emotional negativity without motor responses to noxious stimuli with occasional quieting in response to prosodic stimuli. All patients had whole-brain averaged global metabolism levels below 50% of normal. Patient 1, however, demonstrated preserved islands of increased metabolism in the posterior frontal and posterior temporal lobes, as well as MEG activations of Heschl's gyrus all located in the left hemisphere. In patient 2, selected increased metabolism was confined to the frontal poles and related subcortical structures. MRI in patient 3 demonstrated severe, bilateral post-traumatic cerebral atrophy. PET metabolism was diffusely reduced to 40% of normal but MEG evoked potentials indicated early and late sensory processing with abnormal later evoked components. The correlation of fragmentary behaviour with preserved metabolic and physiologic activity in cortical and subcortical regions known to support specific modular functions is novel. The finding demonstrates the capacity of severely damaged brains to partially express surviving modular functions without evidence of integrative processes that would be necessary to produce consciousness. We conclude that the mere expression of isolated neuropsychologic activity by isolated modules is insufficient to generate consciousness in overwhelmingly damaged brains.

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OBJECTIVE: A reduction of diabetes-related blindness was declared a primary objective for Europe (St. Vincent Declaration). We collected data about incidence rates of blindness in the diabetic population compared with the nondiabetic population. Up to now, such data are scarce-even worldwide. RESEARCH DESIGN AND METHODS: A complete list of newly registered blindness allowance recipients was drawn up in the district of Württemberg-Hohenzollern, Germany, between 1990 and 1993. From these data, we estimated age-specific and standardized incidence rates of blindness in the entire, the diabetic, and the nondiabetic population, as well as relative and attributable risks due to diabetes. RESULTS: There were 2,714 people meeting the inclusion criteria; 1,823 (67.2%) were female and 781 (28.8%) had diabetes. In 318 subjects, diabetes was likely to be the only cause of blindness; in 192 subjects, it was one of several contributory causes. Age of women was 73.9 +/- 19.4 years (mean +/- SD) and of men 63.3 +/- 25.5 years. Results standardized to the (West) German population are as follows: incidence rates (per 100,000 person-years): total population: 13.5; diabetic population: 60.6; nondiabetic population: 11.6; relative risk: 5.2; attributable risk among exposed: 0.81; and population attributable risk: 0.14. The relative risks decreased considerably with increasing age. When the study is repeated to monitor the St. Vincent targets, a reduction in the incidence rate of blindness in the diabetic population by 17% will be detected with 95% power. CONCLUSIONS: Great relative and attributable risks, especially in younger age-groups, indicate the need for increased attention to preventive measures for microvascular complications.

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Clinical efforts in stroke prevention have measurably reduced the incidence of stroke in persons experiencing a number of risk factors. Clinical efforts to reduce stroke size once the process starts, however, have been disappointing. A variety of agents aimed at blocking the effects of excitotoxic neurotransmitters or interfering with intracellular calcium entry have been tested but with little success on clinical outcome. Satisfactory explanation of the paradox between animal and clinical outcome studies has not been forthcoming. Accordingly, clinical investigators are exploring the potential value of surgical craniectomy in efforts to improve the presently devastated outcome that marks the course of severe, large acute cerebral infarctions.

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BACKGROUND: There is only a little information about survival in newly registered blind subjects. METHODS: A closed cohort of blind subjects (n = 2680, 1803 of them women), newly registered between 1990 and 1993 in the district of Württemberg-Hohenzollern, Germany, was observed for up to 48 months. Mortality was compared to that of the general population. Predictors of mortality within that cohort were identified by Cox proportional hazards regression analysis. RESULTS: Before 1 February 1994, 582 of the subjects had died. Diabetes had been diagnosed in 772 of the subjects, 226 of them died. The overall incidence rate of death was 12179 per 100,000 per year. The probability of survival after 47 months was 0.64 (95% confidence interval (CI): 0.59-0.70) in the non-diabetic, and 0.46 (95% CI: 0.37-0.55) in the diabetic subjects. Predictors of mortality in the regression model were age (risk ratio [RR] per year of age 1.047), sex (RR for men 1.247) and diabetes (RR when blindness was unrelated to diabetes: 1,448, RR when diabetes was the only cause of blindness: 2,253). Compared with the entire population, mortality was considerably increased in the blind cohort (comparative mortality figure [CMF] 4.79), particularly in individuals with diabetes (CMF = 6.55). The relative risks decreased with increasing age. CONCLUSIONS: Overall mortality in this cohort was high, even higher than in previous studies on the mortality of the blind. Diabetes increased the risk of death. In addition, the cause of blindness in diabetic individuals was a major predictor of mortality.

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A 65-year-old man with no past history of violent or criminal behavior abruptly strangled his wife after she scratched his face during a domestic argument. He appeared emotionally blunted and lacked insight into the motivations for his violent actions. The presence of left-sided cerebral dysfunction was initially suggested by subtly decreased dexterity of his dominant right hand. A magnetic resonance image (MRI) revealed a large arachnoid cyst centered in his left Sylvian fissure that effaced ventral frontal, anterior temporal and insular cortical gyri. The left middle cerebral artery was displaced relative to an earlier study, providing indirect evidence that the cyst had enlarged during his adult life. Neuropsychological testing indicated generally intact cognitive abilities except for mild impairment on tests of prospective memory and executive functions. He was found to have intermittently decreased EEG amplitude in the left fronto-temporal region. Positron emission tomography (PET) revealed significantly reduced resting glucose metabolism in the left frontal and temporal lobes. He was also found to have pathological diminution of autonomic responses to affectively charged visual stimuli, a phenomenon previously reported in patients with ventromedial frontal lobe injury and acquired disturbances of social conduct. In light of these findings, we suggest that his violent behavior represents stimulus-bound aggression, triggered by a novel physical threat and unchecked by learned social restraints owing to the presence of ventral prefrontal dysfunction.

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The clinical utility of selected brief cognitive screening instruments in detecting dementia in an elderly nursing home population was examined. One hundred twenty nursing home residents (mean age 87.9) were administered the Mini-Mental State Exam (MMSE) and the Modified Mini-Mental State Exam (3MS). The majority of the subjects (75%) were also administered the Dementia Rating Scale (DRS). Both clinically diagnosed demented (n = 57) and non-demented (n = 63) subjects participated in the study. Dementia was diagnosed in accordance with DSM-III-R criteria by physicians specializing in geriatric medicine. Using standard cutoffs for impairment, the 3MS, MMSE, and DRS achieved high sensitivity (82% to 100%) but low specificity (33% to 52%) in the detection of dementia among nursing home residents. Positive predictive values ranged from 52% to 61%, and negative predictive values from 77% to 100%. Higher age, lower education, and history of depression were significantly associated with misclassification of non-demented elderly subjects. Receiver Operating Characteristic (ROC) curve analyses revealed optimal classification of dementia with cutoff values of 74 for the 3MS, 22 for the MMSE, and 110 for the DRS. The results suggest that the 3MS, MMSE, and DRS do not differ significantly with respect to classification accuracy of dementia in a nursing home population. Elderly individuals of advanced age (i.e., the oldest-old) with lower education and a history of depression appear at particular risk for dementia misclassification with these instruments. Revised cutoff values for impairment should be employed when these instruments are applied to elderly residents of nursing homes and the oldest-old.

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Current concepts of brain herniation have depended largely on correlating clinical signs and symptoms with indirect radiographic studies and the results of postmortem neuropathology. This article describes measurements on midsagittal magnetic resonance imaging (MRI) scans that distinctly define normal and abnormal rostral-caudal relationships between the diencephalic-mesencephalic junction and the plane of the tentorial incisura, herein termed the incisural line. We similarly provide quantitative MRI scan measurements relating the cerebellum and the plane of the foramen magnum, termed the foramen magnum line. Measurements from 156 midsagittal and 63 coronal MRI scans performed on 123 normal adults, placed the iter of the aqueduct 0.2 +/- 0.8 mm (mean +/- SD) below the incisural line and the cerebellar tonsils 0.1 +/- 2.1 mm below the foramen magnum line. Defining 2 SD from these norms as abnormal, 23 patients with intracranial mass or obstructive lesions showed 4 distinct patterns of brain herniation, i.e., upward or downward transtentorial shift with or without accompanying cerebellar tonsillar herniation. Five patients with posterior fossa masses demonstrated displacement of the iter above the incisura ranging from 1.6 to 6.3 mm. Eighteen patients with supratentorial masses demonstrated displacement of the iter ranging from 2.0 to 11.0 mm below the incisura. Two-thirds of patients with upward and one-half of those with downward transtentorial shift had concurrent tonsillar herniation. In acute illnesses, MRI scan changes anticipated or confirmed clinical signs of brain herniation. In chronic cases, clinical and MRI scans correlated less well, with MRI sometimes revealing major degrees of anatomical herniation well in advance of clinical abnormalities.

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Two-thirds of stiff-man syndrome (SMS) patients harbor an autoantibody specific for a 64-kD species of glutamic acid decarboxylase (GAD), the rate-limiting enzyme in GABA synthesis. We assayed SMS antisera from two patients with SMS for the presence of anti-GAD antibodies using Western blot, immunohistochemical, and enzymatic analyses. Both SMS antisera recognized an 80-kD antigen present in human and rat neuronal extracts, and failed to recognize the 64-kD GAD species. Immunohistochemistry demonstrated neuronal binding identical to that reported with anti-GAD antibodies. Both sera depleted GAD activity from brain extracts. Our analysis indicates that these SMS antisera differ from previously reported SMS antisera by recognizing a novel 80-kD antigen, and suggests that they contain antibodies directed against either a species of GAD different in size from the 64-kD enzyme, or a protein that co-immunoprecipitates with GAD.

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The three-compartment model of brain acid-base regulation postulates that under circumstances of changing function or disease, hydrogen ion concentrations may differ considerably in the interstitial space (ISS), the neurons and the glial cells. During hyperglycemia plus profound ischemia, for example, direct measurements by microelectrodes followed by intracellular HRP staining show that intraglial pH can fall transiently as low as 3.9, although more often the nadir drops to the 4.5-5.5 range. Concurrently, ISS-pH and, by calculation, neuronal pH fails to and remains constant (but not necessarily the same) at pH 6.2. By contrast, during spreading depression, ISS and intraglial pH at first move rapidly and transiently in opposite directions, ISS [H+] rising, intraglial falling. These two then gradually stabilize, whereas neuronal pH remains substantially more steady and near normal, shifting only minimally from resting baseline levels over several minutes' time. Similar but less pronounced effects follow direct electrical stimulation. The net change represents complex biophysical transmembrane and buffering mechanisms that appear to guard neuronal homeostasis. Studies carried out on embryonic rat forebrain neurons and glia show that these cells have considerably different vulnerabilities to extracellular acidity depending on the anionic nature of the acid in the bathing medium. In cultures to which HCI was added to the medium, neurons and neuronal processes almost all survived ten minute exposures to pH 3.8, whereas glial cells succumbed after ten minute exposures at pH not lower than 4.2.(ABSTRACT TRUNCATED AT 250 WORDS)

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