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Using healthy adult participants, seven measures of heart rate variability were obtained simultaneously from four devices in five behavioral conditions. Two devices were ECG-based and two utilized photoplethysmography. The 140 numerical values (measure, condition, device) are presented. The comparative operational reliability of the four devices was assessed, and it was found that the two ECG-base devices were more reliable than the photoplethysmographic devices. The interchangeability of devices was assessed by determining the between-device Limits of Agreement. Intraclass correlation coefficients were determined and used to calculate the standard error of measurement and the Minimal Detectable Difference. The Minimal Detectable Difference, MDD, quantifies the smallest statistically significant change in a measure and is therefore critical when HRV measures are used longitudinally to assess treatment response or disease progression.

Military service members (SMs) returning from combat are at high risk of developing neuropsychiatric conditions such as posttraumatic stress disorder (PTSD) and major depression. Symptom dynamics following reintegration into civilian life may be magnified over time such that some SMs present with delayed onset and may not reach a diagnostic threshold for months to years. Monitoring the trajectory of mental health in the aftermath of combat trauma can therefore be particularly important in enhancing diagnosis. In this study, we investigated the possible utility of the P300 event-related potential (ERP) as an objective marker for monitoring post-trauma mental health. SMs recently returned from a combat deployment were recruited to undergo a baseline assessment, with subsequent follow-up assessment at 6 or 12 months later. At each assessment, ERPs were recorded using a conventional visual oddball task and a set of psychological scores assessing PTSD, depression, and psychosocial functioning were obtained. We observed that the individuals with overall improved psychological scores at follow-up had increased P300 amplitude and shortened P300 latency, and the individuals with overall worsened psychological scores at follow-up had prolonged P300 latency. The degree of change in aggregate psychological score was significantly correlated with the magnitude of change in P300 amplitude (r = -0.72, p 0.0001) and latency (r = 0.42, p = 0.0201). These findings suggest that the P300 may be utilized as a quantitative biomarker for tracking the changes of mental health longitudinally. It may offer clinicians an objective tool for the assessment of the dynamics of mental health following trauma, and perhaps also for monitoring recovery during treatment.

Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) may share common symptom and neuropsychological profiles in military service members (SMs) following deployment; while a connection between the two conditions is plausible, the relationship between them has been difficult to discern. The intent of this report is to enhance our understanding of the relationship between findings on structural and functional brain imaging and symptoms of PTSD. Within a cohort of SMs who did not meet criteria for PTSD but were willing to complete a comprehensive assessment within 2 months of their return from combat deployment, we conducted a nested case-control analysis comparing those with combat-related mTBI to age/gender-matched controls with diffusion tensor imaging, resting state functional magnetic resonance imaging and a range of psychological measures. We report degraded white matter integrity in those with a history of combat mTBI, and a positive correlation between the white matter microstructure and default mode network (DMN) connectivity. Higher clinician-administered and self-reported subthreshold PTSD symptoms were reported in those with combat mTBI. Our findings offer a potential mechanism through which mTBI may alter brain function, and in turn, contribute to PTSD symptoms.

Traumatic brain injury, depression and posttraumatic stress disorder (PTSD) are neurocognitive syndromes often associated with impairment of physical and mental health, as well as functional status. These syndromes are also frequent in military service members (SMs) after combat, although their presentation is often delayed until months after their return. The objective of this prospective cohort study was the identification of independent predictors of neurocognitive syndromes upon return from deployment could facilitate early intervention to prevent disability. We completed a comprehensive baseline assessment, followed by serial evaluations at three, six, and 12 months, to assess for new-onset PTSD, depression, or postconcussive syndrome (PCS) in order to identify baseline factors most strongly associated with subsequent neurocognitive syndromes. On serial follow-up, seven participants developed at least one neurocognitive syndrome: five with PTSD, one with depression and PTSD, and one with PCS. On univariate analysis, 60 items were associated with syndrome development at p < 0.15. Decision trees and ensemble tree multivariate models yielded four common independent predictors of PTSD: right superior longitudinal fasciculus tract volume on MRI; resting state connectivity between the right amygdala and left superior temporal gyrus (BA41/42) on functional MRI; and single nucleotide polymorphisms in the genes coding for myelin basic protein as well as brain-derived neurotrophic factor. Our findings require follow-up studies with greater sample size and suggest that neuroimaging and molecular biomarkers may help distinguish those at high risk for post-deployment neurocognitive syndromes.

Measuring neuronal activity with electrophysiological methods may be useful in detecting neurological dysfunctions, such as mild traumatic brain injury (mTBI). This approach may be particularly valuable for rapid detection in at-risk populations including military service members and athletes. Electrophysiological methods, such as quantitative electroencephalography (qEEG) and recording event-related potentials (ERPs) may be promising; however, the field is nascent and significant controversy exists on the efficacy and accuracy of the approaches as diagnostic tools. For example, the specific measures derived from an electroencephalogram (EEG) that are most suitable as markers of dysfunction have not been clearly established. A study was conducted to summarize and evaluate the statistical rigor of evidence on the overall utility of qEEG as an mTBI detection tool. The analysis evaluated qEEG measures/parameters that may be most suitable as fieldable diagnostic tools, identified other types of EEG measures and analysis methods of promise, recommended specific measures and analysis methods for further development as mTBI detection tools, identified research gaps in the field, and recommended future research and development thrust areas. The qEEG study group formed the following conclusions: (1) Individual qEEG measures provide limited diagnostic utility for mTBI. However, many measures can be important features of qEEG discriminant functions, which do show significant promise as mTBI detection tools. (2) ERPs offer utility in mTBI detection. In fact, evidence indicates that ERPs can identify abnormalities in cases where EEGs alone are non-disclosing. (3) The standard mathematical procedures used in the characterization of mTBI EEGs should be expanded to incorporate newer methods of analysis including non-linear dynamical analysis, complexity measures, analysis of causal interactions, graph theory, and information dynamics. (4) Reports of high specificity in qEEG evaluations of TBI must be interpreted with care. High specificities have been reported in carefully constructed clinical studies in which healthy controls were compared against a carefully selected TBI population. The published literature indicates, however, that similar abnormalities in qEEG measures are observed in other neuropsychiatric disorders. While it may be possible to distinguish a clinical patient from a healthy control participant with this technology, these measures are unlikely to discriminate between, for example, major depressive disorder, bipolar disorder, or TBI. The specificities observed in these clinical studies may well be lost in real world clinical practice. (5) The absence of specificity does not preclude clinical utility. The possibility of use as a longitudinal measure of treatment response remains. However, efficacy as a longitudinal clinical measure does require acceptable test–retest reliability. To date, very few test–retest reliability studies have been published with qEEG data obtained from TBI patients or from healthy controls. This is a particular concern because high variability is a known characteristic of the injured central nervous system.

The Integrated Neuropsychiatric Assessment System is a portable platform for cognitive neurodynamic research and for clinical evaluations. It provides simultaneous acquisition of heart rate variability, quantitative electroencephalography and event related potentials during a neuropsychological assessment. The analysis protocol includes measures derived from dynamical systems theory including analysis of causal networks, event-dependent interregional synchronization and small world modeling.

Previous studies have demonstrated that exposure to convulsive doses of hyperbaric oxygen (HBO) increases sensitivity to seizures in re-exposures. Because brain derived neurotrophic factor (BDNF) is induced after a variety of seizures and increases cell excitability, it may contribute to the mechanism of sensitization. In this study, a fast induction in BDNF mRNA 2 hr after seizures and a temporary increase in BDNF protein 1 day after seizures induced by 100% O2 at 5 atm (gauge pressure) were demonstrated in the rat cortex. To determine whether an elevation in BDNF protein level can modify sensitivity to the toxic effect of HBO, recombinant BDNF (12 μg) was injected into cerebral ventricles 30 min prior to exposure. Administration of exogenous BDNF significantly shortened latent time to seizures in HBO exposures. We propose that upregulation of BDNF expression in the brain after seizures may contribute to sensitization to HBO toxicity.

Metabolic integrity of glial cells in field CA1 of the guinea pig hippocampus is critical to maintenance of synaptic transmission (Keyser and Pellmar [1994] Glia 10:237-243). To determine if this tight glial-neuronal coupling is equally important in other brain regions, we compared the effect of fluoroacetate (FAC), a glial specific metabolic blocker, on synaptic transmission in field CA1 to synaptic transmission in area dentata (DG). FAC was significantly more effective in decreasing synaptic potentials in CA1 than in DG. A similar regional disparity in the FAC-induced decrease in ATP levels was evident. Isocitrate, a glial specific metabolic substrate, prevented the FAC-induced synaptic depression in both CA1 and DG. The results suggest that glia of CA1 and dentate respond differently to metabolic challenge. Modulation of this glial-neuronal coupling could provide a regionally specific mechanism for synaptic plasticity. Additionally, site-specific glial-neuronal interactions can impact on a variety of physiological and pathophysiological conditions.

The identification and longitudinal assessment of traumatic brain injury presents several challenges. Because these injuries can have subtle effects, efforts to find quantitative physiological measures that can be used to characterize traumatic brain injury are receiving increased attention. The results of this research must be considered with care. Six reasons for cautious assessment are outlined in this paper. None of the issues raised here are new. They are standard elements in the technical literature that describes the mathematical analysis of clinical data. The purpose of this paper is to draw attention to these issues because they need to be considered when clinicians evaluate the usefulness of this research. In some instances these points are demonstrated by simulation studies of diagnostic processes. We take as an additional objective the explicit presentation of the mathematical methods used to reach these conclusions. This material is in the appendices. The following points are made: (1) A statistically significant separation of a clinical population from a control population does not ensure a successful diagnostic procedure. (2) Adding more variables to a diagnostic discrimination can, in some instances, actually reduce classification accuracy. (3) A high sensitivity and specificity in a TBI versus control population classification does not ensure diagnostic successes when the method is applied in a more general neuropsychiatric population. (4) Evaluation of treatment effectiveness must recognize that high variability is a pronounced characteristic of an injured central nervous system and that results can be confounded by either disease progression or spontaneous recovery. A large pre-treatment versus post-treatment effect size does not, of itself, establish a successful treatment. (5) A procedure for discriminating between treatment responders and non-responders requires, minimally, a two phase investigation. This procedure must include a mechanism to discriminate between treatment responders, placebo responders, and spontaneous recovery. (6) A search for prodromes of neuropsychiatric disorders following traumatic brain injury can be implemented with these procedures.

Psychophysiological investigations of traumatic brain injury (TBI) are being conducted for several reasons, including the objective of learning more about the underlying physiological mechanisms of the pathological processes that can be initiated by a head injury. Additional goals include the development of objective physiologically based measures that can be used to monitor the response to treatment and to identify minimally symptomatic individuals who are at risk of delayed onset neuropsychiatric disorders following injury. Research programs studying TBI search for relationships between psychophysiological measures, particularly ERP component properties (e.g. timing, amplitude, scalp distribution), and a participant’s clinical condition. Moreover, the complex relationships between brain injury and psychiatric disorders are receiving increased research attention, and ERP technologies are making contributions to this effort. This review has two objectives supporting such research efforts. The first is to review evidence indicating that traumatic brain injury is a significant risk factor for post-injury neuropsychiatric disorders. The second objective is to introduce ERP researchers who are not familiar with neuropsychiatric assessment to the instruments that are available for characterizing traumatic brain injury, post-concussion syndrome, and psychiatric disorders. Specific recommendations within this very large literature are made. We have proceeded on the assumption that, as is typically the case in an ERP laboratory, the investigators are not clinically qualified and that they will not have access to participant medical records.

Acute exposure to hyperbaric oxygen (HBO) can result in toxicity to the central nervous system (CNS). The most onerous manifestation of CNS oxygen toxicity is the onset of generalized tonic-clonic seizures. HBO-induced convulsions are of particular importance to the Navy, as it is a limiting factor in the duration of diving missions involving surface supplied oxygen and use of the LAR V and MK-15/16 closed-circuit SCUBA apparatus, and the application of HBO medical treatment for decompression sickness. The causal mechanism of HBO-induced seizures is presently unknown. Melatonin has not been tested in its capacity as an anti-convulsant in HBO conditions likely to produce seizures (6 atmospheres absolute). The goal of this research was to examine melatonin prophylaxis in HBO conditions that reliably produce CNS toxicity.

Previous studies have demonstrated that exposure to convulsive doses of hyperbaric oxygen (HBO) increases sensitivity to seizures in re-exposures. Because brain derived neurotrophic factor (BDNF) is induced after a variety of seizures and increases cell excitability, it may contribute to the mechanism of sensitization. In this study, a fast induction in BDNF mRNA 2 hr after seizures and a temporary increase in BDNF protein 1 day after seizures induced by 100% O2 at 5 atm (gauge pressure) were demonstrated in the rat cortex. To determine whether an elevation in BDNF protein level can modify sensitivity to the toxic effect of HBO, recombinant BDNF (12 microg) was injected into cerebral ventricles 30 min prior to exposure. Administration of exogenous BDNF significantly shortened latent time to seizures in HBO exposures. We propose that upregulation of BDNF expression in the brain after seizures may contribute to sensitization to HBO toxicity.

Nitric oxide is involved in the mechanism of hyperbaric oxygen (HBO(2)) brain toxicity as nitric oxide synthase (NOS) inhibitors delay latent time before the onset of seizures. The purpose of this study was to investigate if seizures affect sensitivity to convulsions during subsequent exposure to HBO(2) and to determine if NOS activity and expression is changed after HBO(2) seizures. Rats were exposed to 5 atm (gauge pressure) 100% O(2) until seizures recorded by electroencephalograph (EEG) and reexposed 1, 2, or 6 days later. Latency to seizures was significantly shorter (P0.05) in animals reexposed 1 or 2 days after the first exposure. Activity of calcium-dependent NOS activity in cortex was significantly higher 1 and 2 days after seizures compared with controls (P0.05), while calcium-independent NOS activity was not changed during the 6-day post-seizure interval. The expression of neuronal NOS (nNOS) protein determined by Western blot was higher 1 and 2 days after seizures (P0.05), while the expression of endothelial (eNOS) and inducible (iNOS) remained unchanged. nNOS upregulation 1 and 2 days after seizures and protection against HBO(2) seizures by nNOS-specific inhibitor 7-nitroindazole (7-NI) suggest possible involvement of NO in the mechanism of increased sensitivity to HBO(2) in reexposures.

The importance of glial cells in controlling the neuronal microenvironment has been increasingly recognized. We now demonstrate that glial cells play an integral role in hippocampal synaptic transmission by using the glial-specific metabolic blocker fluoroacetate (FAC) to selectively inhibit glial cell function. FAC inhibits evoked intracellular postsynaptic potentials (PSPs; IC50 = 39 μM) as well as population PSPs (IC50 = 65 μM) in field CA1 of the guinea pig hippocampal slice. Spontaneous synaptic transmission is concurrently decreased. These effects are time and dose dependent. ATP concentrations in glial but not neuronal elements are also significantly reduced with FAC treatment. Simultaneous application of the metabolic substrate isocitrate with FAC prevents both the reduction in glial ATP concentrations and the decrease in evoked PSPs. Given that isocitrate is selectively taken up by glia, these data further support a glial specific metabolic action of FAC. Additionally, FAC has no postsynaptic effects as peak responses to iontophoretically applied glutamate are unchanged. However, the decay of both iontophoretic and evoked PSPs are prolonged following FAC treatment suggesting inhibition of glutamate uptake may contribute to the FAC-induced depression of synaptic potentials. These results show, for the first time, that glial cells are critical for maintenance of synaptic transmission and suggest a role for glial cells in the modulation of synaptic efficacy. © 1994 Wiley-Liss, Inc.

A novel model of status epilepticus based on the kindling model of epilepsy is described. The model involves the administration of a small dose of pilocarpine (20 mg/kg) to rats that have been previously kindled. Stimulation of these pretreated rats produces seizures which continue uninterrupted for approximately 4 h before spontaneous termination. The electroencephalographic discharge pattern showed characteristic changes in polarity and amplitude throughout the duration of status epilepticus. Behaviorally, the animals showed motor seizures which varied between stages I through IV, with evidence of extensive bilateral hemispheric involvement through much of the seizure episode. Animals that had been partially kindled to stage II seizures did not develop status epilepticus after stimulation when pretreated with pilocarpine, indicating that prior kindling is integral to the development of status epilepticus in this model. Administration of scopolamine was ineffective in terminating the condition when it had begun, suggesting that cholinergic stimulation is necessary for the initiation, but not the maintenance, of status epilepticus. This model holds promise for the study of status epilepticus because the condition develops in a seizure-prone (kindled) rat, and the seizures are self-sustaining, without the presence of exogenous chemicals or neurotoxins.