Auditory evoked brain potentials as markers of chronic effects of mild traumatic brain injury in mid-life.

OBJECTIVE: Auditory event-related potential (ERP) correlates of pre-dementia in late-life may also be sensitive to chronic effects of mild traumatic brain injury (mTBI) in mid-life. In addition to mTBI history, other clinical factors may also influence ERP measures of brain function. This study's objective was to evaluate the relationship between mTBI history, auditory ERP metrics, and common comorbidities. METHODS: ERPs elicited during an auditory target detection task, psychological symptoms, and hearing sensitivity were collected in 152 combat-exposed veterans and service members, as part of a prospective observational cohort study. Participants, with an average age of 43.6 years, were grouped according to positive (n = 110) or negative (n = 42) mTBI history. Positive histories were subcategorized into repetitive mTBI (3 + ) (n = 40) or non-repetitive (1-2) (n = 70). RESULTS: Positive history of mTBI was associated with reduced N200 amplitude to targets and novel distractors. In participants with repetitive mTBI compared to non-repetitive and no mTBI, P50 was larger in response to nontargets and N100 was smaller in response to nontargets and targets. Changes in N200 were mediated by depression and anxiety symptoms and hearing loss, with no evidence of a supplementary direct mTBI pathway. CONCLUSIONS: Auditory brain function differed between the positive and negative mTBI groups, especially for repetitive injury, which implicated more basic, early auditory processing than did any mTBI exposure. Symptoms of internalizing psychopathology (depression and anxiety) and hearing loss are implicated in mTBI's diminished brain responses to behaviorally relevant and novel stimuli. SIGNIFICANCE: A mid-life neurologic vulnerability conferred by mTBI, particularly repetitive mTBI, may be detectable using auditory brain potentials, and so auditory ERPs are a target for study of dementia risk in this population.

Prospective Memory in Service Members with Mild Traumatic Brain Injury.

INTRODUCTION: Prospective memory (PM) is the ability to remember the intention to perform an action in the future. Following mild traumatic brain injury (mTBI), the brain structures supporting such PM may be compromised. PM is essential for remembering activities specific to TBI survivors that promote recovery, such as following doctors' orders, taking necessary medications, completing physical rehabilitation exercises, and maintaining supportive social relationships. Since the year 2000, more than 315,897 US Service Members are reported to have sustained an mTBI1, yet little has been done to address possible PM concerns. Therefore, identifying impaired PM and interventions that may ameliorate such deficits is important. The primary aim of this study was to determine whether task encoding using implementation intentions leads to better PM performance than encoding using rote rehearsal in Service Members with mTBI (n = 35) or with bodily injuries but no TBI (n = 8) at baseline and 6 months later. MATERIALS AND METHOD: Participants were randomized to one of the two encoding conditions. They were asked to remember to complete a series of four tasks over the course of a 2-hour event-related potential session and to contact a staff member during a specified 2-hour window later that day. PM performance was assessed based on completion of each task at the appropriate time. IRB approval was obtained from The Catholic University of America, Walter Reed National Military Medical Center, and Ft. Belvoir Community Hospital. RESULTS: Service Members with mTBI using implementation intentions outperformed those using rote rehearsal. The effect of injury type and the interaction between encoding condition and injury type did not yield differences that were statistically significant. CONCLUSIONS: The results suggest that implementation intentions may be a useful PM remediation strategy for those who have sustained mTBI. Future research should validate these findings in a larger sample.

Safety of atomoxetine in combination with intravenous cocaine in cocaine-experienced participants.

OBJECTIVES: Atomoxetine has been considered as an agonist replacement therapy for cocaine. We investigated the safety of the interaction of atomoxetine with cocaine and also whether cognitive function was affected by atomoxetine during short-term administration. METHODS: In a double-blind placebo-controlled inpatient study of 20 cocaine-dependent volunteers, participants received atomoxetine 80 mg daily followed by 100 mg daily for 5 days each. On the fourth and fifth day at each dose, cocaine (20 and 40 mg) was infused intravenously in sequential daily sessions. RESULTS: Preinfusion mean systolic pressures showed a small but statistically significant difference between placebo and both doses of atomoxetine. Preinfusion mean diastolic pressures were significant between placebo and atomoxetine 80 mg only. The diastolic pressure response to 40 mg cocaine was statistically significant only between the 80- and 100-mg atomoxetine doses. All electrocardiogram parameters were unchanged. Visual Analog Scale (VAS) scores for "bad effect" in the atomoxetine group were significantly higher at baseline, then declined, and for "likely to use" declined with atomoxetine treatment. On the Addiction Research Center Inventory, the atomoxetine group scored significantly lower on amphetamine, euphoria, and energy subscales (P < 0.0001). Other VAS descriptors, Brief Substance Craving Scale, Profile of Moods State, and Brief Psychiatric Rating Scale showed no differences. Atomoxetine did not affect cocaine pharmacokinetics. In tests of working memory, sustained attention, cognitive flexibility, and decision-making, atomoxetine improved performance on the visual n-back task. There were no differences in any pharmacokinetic parameters for cocaine with atomoxetine. CONCLUSIONS: Atomoxetine was tolerated safely by all participants. Certain cognitive improvements and a dampening effect on VAS scores after cocaine were observed, but should be weighed against small but significant differences in hemodynamic responses after atomoxetine.

Evaluation of traumatic brain injury: brain potentials in diagnosis, function, and prognosis.

The focus of this review is an analysis of the use of event-related brain potential (ERP) abnormalities as indices of functional pathophysiology in survivors of traumatic brain injury (TBI). TBI may be the most prevalent but least understood neurological disorder in both civilian and military populations. In the military, thousands of new brain injuries occur yearly; this lends considerable urgency to the use of highly sensitive ERP tools to illuminate brain changes and to address remediation issues. We review the processes thought to be indexed by the cognitive components of the ERP and outline the rationale for applying ERPs to evaluate deficits after TBI. Studies in which ERPs were used to clarify the nature of cognitive complaints of TBI survivors are reviewed, emphasizing impairment in attention, information processing, and cognitive control. Also highlighted is research on the application of ERPs to predict emergence from coma and eventual outcome. We describe primary blast injury, the leading cause of TBI for active duty military personnel in present day warfare. The review concludes with a description of an ongoing investigation of mild TBI, aimed at using indices of brain structure and function to predict the course of posttraumatic stress disorder. An additional goal of this ongoing investigation is to characterize the structural and functional sequelae of blast injury.

Brain potential indices of novelty processing are associated with preference for amphetamine.

A behavioral drug preference procedure was used to identify two groups of healthy individuals. One group preferred 10 mg of d-amphetamine over placebo (Choosers) and the other preferred placebo (Nonchoosers). In separate sessions, participants were administered placebo, 10, and 15 mg of d-amphetamine, and event-related brain potentials (ERPs) were recorded while participants performed two 3-stimulus oddball tasks. The effect of d-amphetamine on P3a, an ERP index of the orienting response, differed between groups: In Choosers, target stimuli elicited P3a after d-amphetamine but not after placebo; in Nonchoosers, the drug had no effect on P3a. Moreover, two group differences were evident after placebo and were unaffected by d-amphetamine. (1) N100 was larger in Nonchoosers than in Choosers, suggesting that Nonchoosers were more attentive than Choosers to the physical features of the stimuli. (2) The reorienting negativity (RON) elicited by targets in both tasks and by rare nontargets in a novelty oddball task (i.e., novel sounds) was larger in Nonchoosers than in Choosers. This suggests that Nonchoosers more effectively refocused attention on the task after distraction. It is hypothesized that these processing differences reflect a group difference in the balance between midbrain dopamine function and ascending cholinergic influences. The findings have implications for vulnerability to addiction and illustrate the promise of ERPs in parsing elemental phenotypes.

When it's time for a change: failures to track context in schizophrenia.

INTRODUCTION: Reduction of P300 event-related potential amplitude in schizophrenia is perhaps the most replicated biological reflection of the illness. P300 is typically elicited by infrequent deviant events that are imbedded in a series of identical frequent standard events. Deviants have features that explicitly distinguish them from standards, whereas standards can be distinguished from each other based on their local sequential probabilities within the stimulus series. The improbable occurrence of a standard should generate a P300, but only if the implicit local context generated by the recent stimulus history is processed. METHOD: To assess the ability of schizophrenia patients to process this implicit contextual information, ERPs were elicited from 22 controls and 16 schizophrenia patients during an auditory oddball task containing infrequent target tones (15%) and novel distracter sounds (15%) imbedded pseudo-randomly in a series of standard tones (70%). Consecutively presented standards following deviant stimuli varied in sequential probability from p=1.0 for the 1st standard to p=0.16 for the 4th consecutive standard. RESULTS: Patients compared to controls demonstrated smaller P300 (P3a) to the fourth consecutive standard. However, in controls but not patients a contingent negative variation (CNV) was observed prior to the fourth standard, and an N2b/mismatch negativity (MMN) was observed following it. CONCLUSIONS: These outcomes suggest that patients are deficient in using the implicit context established by recent stimulus history to anticipate that an otherwise standard stimulus was unlikely and its occurrence unexpected.

Evidence for a new late positive ERP component in an attended novelty oddball task.

In attended novelty oddball tasks, rare nontarget stimuli can elicit two late positive ERP components: P3a and P300. In passive oddball tasks, P300 is not elicited by these stimuli. In passive tasks, however, P3a is accompanied by another positive component, termed eP3a, which may have evaded detection in attended oddball tasks because of its spatiotemporal overlap with P300. To address this, temporal-spatial principal components analysis was used to quantify ERPs recorded in attended three-tone and novelty oddball tasks. As expected, novel stimuli elicited both P3a and P300. The analysis also identified a third component, evident in novelty ERPs as an inflection on the leading edge of P3a. This component has the same antecedent conditions as P3a, but is earlier and more centrally distributed. Its spatiotemporal characteristics suggest that it may be the eP3a component recently described in passive oddball tasks.

Event-related potentials in clinical research: guidelines for eliciting, recording, and quantifying mismatch negativity, P300, and N400.

This paper describes recommended methods for the use of event-related brain potentials (ERPs) in clinical research and reviews applications to a variety of psychiatric and neurological disorders. Techniques are presented for eliciting, recording, and quantifying three major cognitive components with confirmed clinical utility: mismatch negativity (MMN), P300, and N400. Also highlighted are applications of each of the components as methods of investigating central nervous system pathology. The guidelines are intended to assist investigators who use ERPs in clinical research, in an effort to provide clear and concise recommendations and thereby to standardize methodology and facilitate comparability of data across laboratories.

Assessment of the attention impairment in absence epilepsy: comparison of visual and auditory P300.

We report an investigation of P300 measures of information processing in patients with generalized epilepsy of the absence type and those with complex partial epilepsy. Studies have demonstrated that absence patients perform more poorly than complex partial patients on behavioral tests of sustained attention (the Continuous Performance Test, or CPT). Duncan [Duncan, C.C., 1988. Application of event-related brain potentials to the analysis of interictal attention in absence epilepsy. In: Myslobodsky, M.S., Mirsky, A.F. (Eds.), Elements of Petit Mal Epilepsy. Peter Lang, New York, pp. 341-364] reported that P300 was significantly reduced in a group of absence patients as compared with healthy controls. The present investigation was undertaken to compare the attention deficit in absence patients to that in complex partial seizure patients. Thus, ERPs were recorded while participants with absence seizure disorder, complex partial seizure disorder, and healthy controls performed auditory and visual versions of the CPT. A significant reduction in the amplitude of P300 on the visual CPT was observed in both groups of seizure patients as compared to controls. In contrast, P300 on the auditory CPT was reduced only in the group with absence seizures. These ERP data support and amplify previous behavioral findings of the impaired capacity of absence patients to mobilize and sustain attentional resources. Auditory sustained attention seems to be more affected by the pathophysiology of absence epilepsy than visual attention. Two possible factors may be involved: (a) There are separate visual and auditory attention systems in the brain, and the latter is more vulnerable than the former [Duncan, C.C., Kosmidis, M.H., Mirsky, A.F., 2005. Closed head injury-related information processing deficits: An event-related potential analysis. Int. J. Psychophysiol. 58, 133-157]; and (b) Auditory processing depends on intact mechanisms in the brainstem, which are dysfunctional in patients with absence seizures.

Closed head injury-related information processing deficits: an event-related potential analysis.

Event-related potentials (ERPs) can elucidate aspects of sensory and cognitive processing that have been compromised due to closed head injury. We present the results of two investigations, one previously unreported, in which we used ERPs to evaluate information processing in head-injury survivors. In the first study, we used visual and auditory reaction time tasks differing in attentional demands to assess processing after head trauma. We found numerous changes in auditory processing in survivors: longer reaction times (but normal accuracy), longer N200 and P300 latencies, and reduced N100 and N200 amplitudes. In contrast, on visual tasks, only reduced N200 amplitude distinguished survivors and controls. To increase attentional demands, in a second study, we administered the continuous performance test (CPT). Survivors performed with lower accuracy than controls on visual and auditory tasks, and their ERPs were characterized by smaller visual and auditory N200s and P300s and smaller auditory N100s. We also present a synthesis, derived from a review of the literature, of closed head-injury effects on ERPs. Our own findings are in agreement with that synthesis. Namely, cognitive ERP components are more sensitive than sensory components to the effects of trauma. Specifically, in survivors, the amplitudes of N200 and P300 are often reduced, and their latencies prolonged. In general, as compared with visual ERPs, auditory ERPs may be more susceptible to the effects of closed head injury, suggesting that the auditory processing system is more vulnerable than the visual system. We conclude by discussing the potential use of ERPs to monitor clinical course and recovery in survivors of closed head injury.

Pathophysiology of mental illness: a view from the fourth ventricle.

The concept of mental disorders as diseases of the brain is as old as the ancient Greek philosopher-physicians. However, for thousands of years, the majority of doctors, as well as laypersons, held strongly to the belief that epilepsy and "madness" (i.e., schizophrenia)--the major disorders discussed in this paper--were caused by demonic "possession." As always, the theory of causation led to apposite therapies: Cast out the devil by whatever means necessary. Later, more enlightened views of etiology led to less punitive "cures," which, to modern sensibilities, still seem barbaric. The 20th century saw the introduction of medications that provide symptomatic relief, if not cures, for seizure disorders and schizophrenia. In this paper, we consider the etiology of absence (petit mal) epilepsy and schizophrenia based on the pathophysiology underlying the shared symptom of impaired sustained attention. We emphasize the role of abnormal functioning of brainstem structures in the region of the fourth ventricle, whether caused by genetic or environmental factors or a combination thereof. Our theorizing relies on the findings of Lindsley, Magoun, and Moruzzi, who delineated the role of the brainstem reticular activating system in sleep, wakefulness, and consciousness. It also relies on the work of Penfield, Jasper, and Gloor, who sought to illuminate the role of brainstem-thalamus-cortical dysfunction in idiopathic generalized epilepsies. We consider evidence from recent studies that emphasize the phasic attentional functions supported by brainstem structures in the region of the fourth ventricle, and possible genetic links among disorders in which impaired attention is a prominent symptom.

Event-related potential assessment of information processing after closed head injury.

We evaluated alterations in information processing after closed head injury as a function of task demands and stimulus modality. Visual and auditory discrimination tasks were administered to 11 survivors of a head injury and 16 matched healthy controls. In auditory tasks, compared with controls, the survivors had smaller N100s, smaller and later N200s, a more posterior scalp distribution of N200, and longer P300 and response latencies. Auditory N200 and P300 correlated highly with duration of unconsciousness. In contrast, in visual tasks, only a reduced N200 in the survivors differentiated the groups. Our results indicate that processing of auditory stimuli, including the perception and discrimination of stimulus features and the evaluation and categorization of stimuli, may be impaired after head trauma. Visual sensory processing may be spared, but higher-order visual processing involved in stimulus classification may be compromised.