Regional cerebral metabolic patterns demonstrate the role of anterior forebrain mesocircuit dysfunction in the severely injured brain

peer reviewedAlthough disorders of consciousness (DOCs) demonstrate widely varying clinical presentations and patterns of structural injury, global down-regulation and bilateral reductions in metabolism of the thalamus and frontoparietal network are consistent findings. We test the hypothesis that global reductions of background synaptic activity in DOCs will associate with changes in the pattern of metabolic activity in the central thalamus and globus pallidus. We compared 32 [18F]fluorodeoxyglucose PETs obtained from severely brain-injured patients (BIs) and 10 normal volunteers (NVs). We defined components of the anterior forebrain mesocircuit on high-resolution T1-MRI (ventral, associative, and sensorimotor striatum; globus pallidus; central thalamus and noncentral thalamus). Metabolic profiles for BI and NV demonstrated distinct changes in the pattern of uptake: ventral and association striatum (but not sensorimotor) were significantly reduced relative to global mean uptake after BI; a relative increase in globus pallidus metabolism was evident in BI subjects who also showed a relative reduction of metabolism in the central thalamus. The reversal of globus pallidus and central thalamus profiles across BIs and NVs supports the mesocircuit hypothesis that broad functional (or anatomic) deafferentation may combine to reduce central thalamus activity and release globus pallidus activity in DOCs. In addition, BI subjects showed broad frontoparietal metabolic down-regulation consistent with prior studies supporting the link between central thalamic/pallidal metabolism and down-regulation of the frontoparietal network. Recovery of left hemisphere frontoparietal metabolic activity was further associated with command following

The Assessment of Conscious Awareness in the Vegetative State

The assessment of patients in the vegetative state is extremely complex and depends frequently on subjective interpretations of the observed spontaneous and volitional behavior. In recent years, a number of studies have demonstrated an important role for functional neuroimaging in the identification of residual cognitive function, and even conscious awareness, in some patients fulfilling the clinical criteria for vegetative state. Such studies, when successful, may be particularly useful where there is concern about the accuracy of the diagnosis and the possibility that residual cognitive function has remained undetected. However, use of these techniques in severely brain-injured persons is methodologically complex and requires careful quantitative analysis and interpretation

A Bayesian statistical analysis of behavioral facilitation associated with deep brain stimulation

Deep brain stimulation (DBS) is an established therapy for Parkinson's Disease and is being investigated as a treatment for chronic depression, obsessive compulsive disorder and for facilitating functional recovery of patients in minimally conscious states following brain injury. For all of these applications, quantitative assessments of the behavioral effects of DBS are crucial to determine whether the therapy is effective and, if so, how stimulation parameters can be optimized. Behavioral analyses for DBS are challenging because subject performance is typically assessed from only a small set of discrete measurements made on a discrete rating scale, the time course of DBS effects is unknown, and between-subject differences are often large. We demonstrate how Bayesian state-space methods can be used to characterize the relationship between DBS and behavior comparing our approach with logistic regression in two experiments: the effects of DBS on attention of a macaque monkey performing a reaction-time task, and the effects of DBS on motor behavior of a human patient in a minimally conscious state. The state-space analysis can assess the magnitude of DBS behavioral facilitation (positive or negative) at specific time points and has important implications for developing principled strategies to optimize DBS paradigms.National Institutes of Health (U.S.)(R01 MH-071847)National Institutes of Health (U.S.) (DP1 OD003646)National Institutes of Health (U.S.)(NS02172)IntElect Medical (Firm

General anesthesia, sleep and coma

In the United States, nearly 60,000 patients per day receive general anesthesia for surgery.1 General anesthesia is a drug-induced, reversible condition that includes specific behavioral and physiological traits — unconsciousness, amnesia, analgesia, and akinesia — with concomitant stability of the autonomic, cardiovascular, respiratory, and thermoregulatory systems.2 General anesthesia produces distinct patterns on the electroencephalogram (EEG), the most common of which is a progressive increase in low-frequency, high-amplitude activity as the level of general anesthesia deepens3,4 (Figure 1Figure 1Electroencephalographic (EEG) Patterns during the Awake State, General Anesthesia, and Sleep.). How anesthetic drugs induce and maintain the behavioral states of general anesthesia is an important question in medicine and neuroscience.6 Substantial insights can be gained by considering the relationship of general anesthesia to sleep and to coma. Humans spend approximately one third of their lives asleep. Sleep, a state of decreased arousal that is actively generated by nuclei in the hypothalamus, brain stem, and basal forebrain, is crucial for the maintenance of health.7,8 Normal human sleep cycles between two states — rapid-eye-movement (REM) sleep and non-REM sleep — at approximately 90-minute intervals. REM sleep is characterized by rapid eye movements, dreaming, irregularities of respiration and heart rate, penile and clitoral erection, and airway and skeletal-muscle hypotonia.7 In REM sleep, the EEG shows active high-frequency, low-amplitude rhythms (Figure 1). Non-REM sleep has three distinct EEG stages, with higher-amplitude, lower-frequency rhythms accompanied by waxing and waning muscle tone, decreased body temperature, and decreased heart rate. Coma is a state of profound unresponsiveness, usually the result of a severe brain injury.9 Comatose patients typically lie with eyes closed and cannot be roused to respond appropriately to vigorous stimulation. A comatose patient may grimace, move limbs, and have stereotypical withdrawal responses to painful stimuli yet make no localizing responses or discrete defensive movements. As the coma deepens, the patient's responsiveness even to painful stimuli may diminish or disappear. Although the patterns of EEG activity observed in comatose patients depend on the extent of the brain injury, they frequently resemble the high–amplitude, low-frequency activity seen in patients under general anesthesia10 (Figure 1). General anesthesia is, in fact, a reversible drug-induced coma. Nevertheless, anesthesiologists refer to it as “sleep” to avoid disquieting patients. Unfortunately, anesthesiologists also use the word “sleep” in technical descriptions to refer to unconsciousness induced by anesthetic drugs.11 (For a glossary of terms commonly used in the field of anesthesiology, see the Supplementary Appendix, available with the full text of this article at NEJM.org.) This review discusses the clinical and neurophysiological features of general anesthesia and their relationships to sleep and coma, focusing on the neural mechanisms of unconsciousness induced by selected intravenous anesthetic drugs.Massachusetts General Hospital. Dept. of Anesthesia and Critical Care, and Pain MedicineNational Institutes of Health (NIH) (Director’s Pioneer Award DP1OD003646)University of Michigan. Dept. of AnesthesiologyNational Institutes of Health (U.S.) (grant HL40881)National Institutes of Health (U.S.) (grant HL65272)James S. McDonnell FoundationNational Institutes of Health (U.S.) (grant HD51912

Correlation between resting state fMRI total neuronal activity and PET metabolism in healthy controls and patients with disorders of consciousness.

INTRODUCTION: The mildly invasive 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is a well-established imaging technique to measure \u27resting state\u27 cerebral metabolism. This technique made it possible to assess changes in metabolic activity in clinical applications, such as the study of severe brain injury and disorders of consciousness. OBJECTIVE: We assessed the possibility of creating functional MRI activity maps, which could estimate the relative levels of activity in FDG-PET cerebral metabolic maps. If no metabolic absolute measures can be extracted, our approach may still be of clinical use in centers without access to FDG-PET. It also overcomes the problem of recognizing individual networks of independent component selection in functional magnetic resonance imaging (fMRI) resting state analysis. METHODS: We extracted resting state fMRI functional connectivity maps using independent component analysis and combined only components of neuronal origin. To assess neuronality of components a classification based on support vector machine (SVM) was used. We compared the generated maps with the FDG-PET maps in 16 healthy controls, 11 vegetative state/unresponsive wakefulness syndrome patients and four locked-in patients. RESULTS: The results show a significant similarity with ρ = 0.75 ± 0.05 for healthy controls and ρ = 0.58 ± 0.09 for vegetative state/unresponsive wakefulness syndrome patients between the FDG-PET and the fMRI based maps. FDG-PET, fMRI neuronal maps, and the conjunction analysis show decreases in frontoparietal and medial regions in vegetative patients with respect to controls. Subsequent analysis in locked-in syndrome patients produced also consistent maps with healthy controls. CONCLUSIONS: The constructed resting state fMRI functional connectivity map points toward the possibility for fMRI resting state to estimate relative levels of activity in a metabolic map

A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is however critical both for basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brain-wide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brain-wide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open access data repository; compatibility with existing resources, and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.Comment: 41 page

Dementias show differential physiological responses to salient sounds.

Abnormal responsiveness to salient sensory signals is often a prominent feature of dementia diseases, particularly the frontotemporal lobar degenerations, but has been little studied. Here we assessed processing of one important class of salient signals, looming sounds, in canonical dementia syndromes. We manipulated tones using intensity cues to create percepts of salient approaching ("looming") or less salient withdrawing sounds. Pupil dilatation responses and behavioral rating responses to these stimuli were compared in patients fulfilling consensus criteria for dementia syndromes (semantic dementia, n = 10; behavioral variant frontotemporal dementia, n = 16, progressive nonfluent aphasia, n = 12; amnestic Alzheimer's disease, n = 10) and a cohort of 26 healthy age-matched individuals. Approaching sounds were rated as more salient than withdrawing sounds by healthy older individuals but this behavioral response to salience did not differentiate healthy individuals from patients with dementia syndromes. Pupil responses to approaching sounds were greater than responses to withdrawing sounds in healthy older individuals and in patients with semantic dementia: this differential pupil response was reduced in patients with progressive nonfluent aphasia and Alzheimer's disease relative both to the healthy control and semantic dementia groups, and did not correlate with nonverbal auditory semantic function. Autonomic responses to auditory salience are differentially affected by dementias and may constitute a novel biomarker of these diseases