The Importance of Therapeutic Time Window in the Treatment of Traumatic Brain Injury

Traumatic brain injury (TBI) is a major cause of death and disability. Despite its importance in public health, there are presently no drugs to treat TBI. Many reasons underlie why drugs have failed clinical trials, one reason is that most drugs to treat TBI lose much of their efficacy before patients are first treated. This review discusses the importance of therapeutic time window; the time interval between TBI onset and the initiation of treatment. Therapeutic time window is complex, as brain injury is both acute and chronic, resulting in multiple drug targets that appear and disappear with differing kinetics. The speed and increasing complexity of TBI pathophysiology is a major reason why drugs lose efficacy as time to first dose increases. Recent Phase III clinical trials treated moderate to severe TBI patients within 4–8 h after injury, yet they turned away many potential patients who could not be treated within these time windows. Additionally, most head trauma is mild TBI. Unlike moderate to severe TBI, patients with mild TBI often delay treatment until their symptoms do not abate. Thus, drugs to treat moderate to severe TBI likely will need to retain high efficacy for up to 12 h after injury; drugs for mild TBI, however, will likely need even longer windows. Early pathological events following TBI progress with similar kinetics in humans and animal TBI models suggesting that preclinical testing of time windows assists the design of clinical trials. We reviewed preclinical studies of drugs first dosed later than 4 h after injury. This review showed that therapeutic time window can differ depending upon the animal TBI model and the outcome measure. We identify the few drugs (methamphetamine, melanocortin, minocycline plus N-acetylcysteine, and cycloserine) that demonstrated good therapeutic windows with multiple outcome measures. On the basis of their therapeutic window, these drugs appear to be excellent candidates for clinical trials. In addition to further testing of these drugs, we recommend that the assessment of therapeutic time window with multiple outcome measures becomes a standard component of preclinical drug testing

A Native Haitian Woman with Unverricht-Lundborg Disease

Unverricht-Lundborg disease (ULD) is an autosomal recessive progressive myoclonic epilepsy. The prevalence is highest in specific European countries and North Africa. Affected individuals have myoclonic and tonic-clonic seizures and a variable degree of ataxia and cognitive impairment. We report a native Haitian woman with ULD who was wheelchair bound due to nearly continuous myoclonic seizures exacerbated by activity and emotional distress. The seizures and their dramatic increase with volitional activity were recorded during video electroencephalography monitoring. Rational antiepileptic drug therapy controlled the seizures well enough for the patient to achieve a level of independence she had not experienced in over 25 years

EEG asymmetry and BIS/BAS among healthy adolescents

Asymmetry in frontal alpha activation (FAA) has been associated with specific behavior patterns. Greater activation in the left frontal cortex is related to "approach" motivation, while greater activation in the right cortex is associated with "withdrawal" motivation. Moreover, resting FAA is stable over time among adults. This stability has not been demonstrated among adolescents, and the correspondence between resting FAA and personality has been inconsistently observed. The present study examined stability of FAA and the association between resting FAA and behavioral activation among adolescents. At baseline and 4 months, 99 adolescents completed a resting electroencephalogram (EEG) and a pencil-and-paper measure of personality (BIS/BAS). FAA showed good stability over time (Intra-class correlation coefficient=0.65, p<0.001), but there was no correlation between FAA and personality. Results are interpreted in light of a capability model of FAA; namely, that asymmetry may emerge under conditions of stimulation and recede during resting

EEG asymmetry and BIS/BAS among healthy adolescents

Asymmetry in frontal alpha activation (FAA) has been associated with specific behavior patterns. Greater activation in the left frontal cortex is related to “approach” motivation, while greater activation in the right cortex is associated with “withdrawal” motivation. Moreover, resting FAA is stable over time among adults. This stability has not been demonstrated among adolescents, and the correspondence between resting FAA and personality has been inconsistently observed. The present study examined stability of FAA and the association between resting FAA and behavioral activation among adolescents. At baseline and 4 months, 99 adolescents completed a resting electroencephalogram (EEG) and a pencil-and-paper measure of personality (BIS/BAS). FAA showed good stability over time (Intra-class correlation coefficient = .65, p < .001), but there was no correlation between FAA and personality. Results are interpreted in light of a capability model of FAA; namely, that asymmetry may emerge under conditions of stimulation and recede during resting