Emotional Modulation of Frontal Alpha Asymmetry - a Novel Biomarker of Mild Traumatic Brain Injury

Objective findings of brain injury or dysfunction are typically lacking in mild traumatic brain injury (MTBI) despite prolonged post-concussion symptoms in some patients. Thus, there is a need for objective biomarkers of MTBI that reflect altered brain physiology underlying subjective symptoms. We have previously reported increased attention to threat-related stimuli in subjects with MTBI, suggesting a physiological vulnerability to depression. Vulnerability to depression has been linked with relatively greater activity of the right than left frontal cortex reflected in inverse pattern in frontal alpha with greater power on the left than right. We investigated whether patients with previous MTBI show this pattern of frontal activity reflected in more negative frontal alpha asymmetry (FAA) scores. Furthermore, in search for potential biomarkers of MTBI, we created a novel index, emotional modulation of FAA (eFAA) and investigated whether it correlates with subjective symptoms. EEG was recorded while subjects with previous MTBI and controls performed a computer-based reaction time task integrating different cognitive executive functions and containing either threat-related or emotionally neutral visual stimuli. Post-concussion symptoms and depression were assessed using the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) and Beck's depression inventory (BDI). Task-induced FAA was assessed and eFAA calculated by subtracting FAA in the context of neutral stimuli from FAA in the context of emotional stimuli. The MTBI group showed FAA scores reflecting relatively greater right-sided frontal activity compared to healthy controls. eFAA differentiated the symptomatic MTBI from non-symptomatic MTBI group and from healthy controls. eFAA also correlated with RPQ and BDI scores. In conclusion, FAA pattern previously linked with vulnerability to depression, was observed in patients with previous MTBI. Furthermore, eFAA has potential as a biomarker of altered affective brain functions in MTBI

The Biochemistry, Ultrastructure, and Subunit Assembly Mechanism of AMPA Receptors

The AMPA-type ionotropic glutamate receptors (AMPA-Rs) are tetrameric ligand-gated ion channels that play crucial roles in synaptic transmission and plasticity. Our knowledge about the ultrastructure and subunit assembly mechanisms of intact AMPA-Rs was very limited. However, the new studies using single particle EM and X-ray crystallography are revealing important insights. For example, the tetrameric crystal structure of the GluA2cryst construct provided the atomic view of the intact receptor. In addition, the single particle EM structures of the subunit assembly intermediates revealed the conformational requirement for the dimer-to-tetramer transition during the maturation of AMPA-Rs. These new data in the field provide new models and interpretations. In the brain, the native AMPA-R complexes contain auxiliary subunits that influence subunit assembly, gating, and trafficking of the AMPA-Rs. Understanding the mechanisms of the auxiliary subunits will become increasingly important to precisely describe the function of AMPA-Rs in the brain. The AMPA-R proteomics studies continuously reveal a previously unexpected degree of molecular heterogeneity of the complex. Because the AMPA-Rs are important drug targets for treating various neurological and psychiatric diseases, it is likely that these new native complexes will require detailed mechanistic analysis in the future. The current ultrastructural data on the receptors and the receptor-expressing stable cell lines that were developed during the course of these studies are useful resources for high throughput drug screening and further drug designing. Moreover, we are getting closer to understanding the precise mechanisms of AMPA-R-mediated synaptic plasticity

Emotional Modulation of Frontal Alpha Asymmetry : a Novel Biomarker of Mild Traumatic Brain Injury

Objective findings of brain injury or dysfunction are typically lacking in mild traumatic brain injury (MTBI) despite prolonged post-concussion symptoms in some patients. Thus, there is a need for objective biomarkers of MTBI that reflect altered brain physiology underlying subjective symptoms. We have previously reported increased attention to threat-related stimuli in subjects with MTBI, suggesting a physiological vulnerability to depression. Vulnerability to depression has been linked with relatively greater activity of the right than left frontal cortex reflected in inverse pattern in frontal alpha with greater power on the left than right. We investigated whether patients with previous MTBI show this pattern of frontal activity reflected in more negative frontal alpha asymmetry (FAA) scores. Furthermore, in search for potential biomarkers of MTBI, we created a novel index, emotional modulation of FAA (eFAA) and investigated whether it correlates with subjective symptoms. EEG was recorded while subjects with previous MTBI and controls performed a computer-based reaction time task integrating different cognitive executive functions and containing either threat-related or emotionally neutral visual stimuli. Post-concussion symptoms and depression were assessed using the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) and Beck’s depression inventory (BDI). Task-induced FAA was assessed and eFAA calculated by subtracting FAA in the context of neutral stimuli from FAA in the context of emotional stimuli. The MTBI group showed FAA scores reflecting relatively greater right-sided frontal activity compared to healthy controls. eFAA differentiated the symptomatic MTBI from non-symptomatic MTBI group and from healthy controls. eFAA also correlated with RPQ and BDI scores. In conclusion, FAA pattern previously linked with vulnerability to depression, was observed in patients with previous MTBI. Furthermore, eFAA has potential as a biomarker of altered affective brain functions in MTBI.publishedVersionPeer reviewe

Orbitofrontal Lesion Alters Brain Dynamics of Emotion-Attention and Emotion-Cognitive Control Interaction in Humans

Patients with lesion to the orbitofrontal cortex (OFC) experience challenges in emotional control and emotion-guided behaviors. The OFC is known to participate in executive functions and attentional control of emotion and our previous research suggests OFC lesion alters the balance between voluntary and involuntary attention and cognitive control within the context of emotion. To better understand how OFC lesion affects the dynamics and interaction of these functions, we studied EEG and performance of 12 patients with lesion to the OFC and 11 control subjects with intact OFC in a Go/NoGo visual reaction time (RT) task with neutral targets and intervening threat-related emotional distractors (Executive RT Test). Event-related potentials (ERPs), specifically N2P3 peak-to-peak amplitude and the following late positive potential (LPP), were used to measure allocation of attention and cognitive control to emotional distractors. Task performance and Behavior Rating Inventory of Executive Functions—Adult version (BRIEF-A) scores were used to assess executive functions. As expected, the Control group showed increased N2P3 amplitude in the context of threat-related distractors, particularly over the right hemisphere, while LPP was not modulated by these distractors. In contrast, patients with OFC lesion showed no such impact of threat-related distractors on N2P3 amplitude but exhibited increased and prolonged left-lateralized impact of threat on LPP in the Go-condition. In NoGo-condition, the N2P3 amplitude was increased in both groups due to threat, but the impact was seen earlier, i.e., at the N2 peak in the OFC group and later at the P3 peak in Controls. The OFC group committed more errors in the Executive RT Test and reported more problems in BRIEF-A, thus both objective and subjective evidence for challenges in executive functions was obtained in patients with orbitofrontal lesion. Furthermore, the time-course of attention allocation and cognitive control towards task-irrelevant emotional stimuli was altered as evidenced by ERPs. We conclude that orbitofrontal lesion is associated with altered neural dynamics underlying the interaction of involuntary attention to emotion and cognitive control. These alterations in brain dynamics may underlie some of the challenges patients encounter in everyday life when emotional events interact with cognitive demands