Pilot Study of Neurological Soft Signs and Depressive and Postconcussive Symptoms During Recovery From Mild Traumatic Brain Injury (mTBI).

Neurological soft signs (NSSs) tap into a variety of perceptual, motor, and cognitive functions. The authors administered a battery of NSSs serially to a group of 14 pilot patients recruited from an emergency room after they experienced a mild traumatic brain injury. Patients were seen within 96 hours after injury, and again 30 and 90 days later. Measures of balance, mood, and postconcussive symptoms and impairment were also obtained. NSSs and balance improved across visits. Across visits, NSSs and balance were not significantly associated with any postconcussive outcome measures, although depressive symptoms were. Initial neurological impairment appeared to predict subsequent residual postconcussive symptoms and impairment, but this result requires replication.

Pilot study of the effect of lipophilic vs. hydrophilic beta-adrenergic blockers being taken at time of intracardiac defibrillator discharge on subsequent PTSD symptoms.

A pathophysiological model of posttraumatic stress disorder (PTSD) posits that an overly strong stress response at the time of the traumatic event leads to overconsolidation of the event's memory in part through a central ß-adrenergic mechanism. We hypothesized that the presence of a ß-blocker in the patient's brain at the time of the traumatic event would reduce the PTSD outcome by blocking this effect. The unpredictable, uncontrollable discharge of an implantable intracardiac defibrillator (ICD) is experienced by most patients as highly stressful, and it has previously been shown to be capable of causing PTSD symptoms. The present pilot study evaluated a convenience sample of 18 male cardiac patients who had been taking either a lipophilic ß-blocker (which penetrates the blood-brain barrier) or a hydrophilic ß-blocker (which does not) at the time of a discharge of their ICD. The self- report PTSD Checklist-Specific Version quantified 17 PTSD symptoms pertaining to the ICD discharge during the month preceding the evaluation. There was a statistical trend for patients who had been taking a lipophilic ß-blocker at the time of the ICD discharge to have (35%) less severe PTSD symptoms than patients who had been taking a hydrophilic ß-blocker (one-tailed p=0.07, g=0.64). Further, prospective, randomized, controlled studies are suggested.

Delayed extinction fails to reduce skin conductance reactivity to fear-conditioned stimuli.

A brief 10-min time delay between an initial and subsequent exposure to extinction trials has been found to impair memory reconsolidation in fear-conditioned rodents and humans, providing a potential means to reduce fearfulness in anxiety disorders and posttraumatic stress disorder (PTSD). The present study used videos of biologically prepared, conditioned stimuli (tarantulas) to test the efficacy of delayed extinction in blocking reconsolidation of conditioned fear in healthy young adults. Strong differential conditioning, measured by skin conductance, was observed among a screened subset of participants during acquisition. However, the delayed-extinction intervention failed to reduce reactivity to the conditioned stimulus paired with the extinction delay. These results are partially consistent with other recent, mixed findings and point to a need for testing other candidate interventions designed to interfere with the reconsolidation process.

Prereactivation propranolol fails to reduce skin conductance reactivity to prepared fear-conditioned stimuli.

Pharmacologic blockade of memory reconsolidation has been demonstrated in fear-conditioned rodents and humans and may provide a means to reduce fearfulness in anxiety disorders and posttraumatic stress disorder. Studying the efficacy of potential interventions in clinical populations is challenging, creating a need for paradigms within which candidate reconsolidation-blocking interventions can be readily tested. We used videos of biologically prepared conditioned stimuli (tarantulas) to test the efficacy of propranolol in blocking reconsolidation of conditioned fear in healthy young adults. Strong differential conditioning, measured by skin conductance, was observed among a screened subset of participants during acquisition. However, subsequent propranolol failed to reduce reactivity to the reactivated conditioned stimulus. These results are consistent with other recent findings and point to a need for testing other candidate drugs.

Pharmacological blockade of memory reconsolidation in posttraumatic stress disorder: three negative psychophysiological studies.

Posttraumatic stress disorder (PTSD) may involve over-consolidated emotional memories of the traumatic event. Reactivation (RP) can return a memory to an unstable state, from which it must be restabilized (reconsolidated) if it is to persist. Pharmacological agents administered while the memory is unstable have been shown to impair reconsolidation. The N-methyl-d-aspartate (NMDA) partial agonist d-cycloserine (DCS) may promote memory destabilization. In the three studies reported here, we investigated whether the ß-adrenergic blocker propranolol or the glucocorticoid (GR) antagonist mifepristone, given at the time of traumatic memory reactivation, could reduce PTSD symptoms and physiological responding during subsequent traumatic imagery. Individuals with PTSD were randomized as follows: Study One: propranolol with memory reactivation (n=10) or without reactivation (n=8); Study Two: reactivation mifepristone (n=13), non-reactivation (NRP) mifepristone (n=15), or double placebo (PL) (n=15); Study Three: reactivation mifepristone plus d-cycloserine (n=16), or two placebos (n=15). Subjects underwent memory retrieval by describing their traumatic event. A week later they engaged in script-driven traumatic mental imagery, while heart rate (HR), skin conductance (SC), and facial electromyogram (EMG) responses were measured. There were no significant group differences in physiological responsivity or change in PTSD symptoms in any of the studies. These results do not support successful blockade of reconsolidation of traumatic memories in PTSD.

Cortical and cerebellar modulation of autonomic responses to loud sounds.

Detecting unexpected environmental change causes modulation of autonomic activity essential for survival. Understanding the neural mechanisms associated with responses to loud sounds may provide insights into the pathophysiology of posttraumatic stress disorder (PTSD), since individuals with PTSD exhibit heightened autonomic responses to unexpected loud sounds. We combined fMRI with autonomic psychophysiological assessment to investigate central and peripheral reactivity to loud tones in 20 healthy participants. Activity in anterior insula, pregenual anterior cingulate cortex, anterior midcingulate cortex, supplementary motor area, supramarginal gyrus, and cerebellar lobules VIII-IX was associated with both tones and concomitant skin conductance responses. Since regions signaling unexpected external events modulate autonomic activity, heightened loud tone autonomic responses in PTSD may reflect sensitization of this "salience" network.