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.

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.

Causal Evidence from Humans for the Role of Mediodorsal Nucleus of the Thalamus in Working Memory.

The mediodorsal nucleus of the thalamus (MD), with its extensive connections to the lateral pFC, has been implicated in human working memory and executive functions. However, this understanding is based solely on indirect evidence from human lesion and imaging studies and animal studies. Direct, causal evidence from humans is missing. To obtain direct evidence for MD's role in humans, we studied patients treated with deep brain stimulation (DBS) for refractory epilepsy. This treatment is thought to prevent the generalization of a seizure by disrupting the functioning of the patient's anterior nuclei of the thalamus (ANT) with high-frequency electric stimulation. This structure is located superior and anterior to MD, and when the DBS lead is implanted in ANT, tip contacts of the lead typically penetrate through ANT into the adjoining MD. To study the role of MD in human executive functions and working memory, we periodically disrupted and recovered MD's function with high-frequency electric stimulation using DBS contacts reaching MD while participants performed a cognitive task engaging several aspects of executive functions. We hypothesized that the efficacy of executive functions, specifically working memory, is impaired when the functioning of MD is perturbed by high-frequency stimulation. Eight participants treated with ANT-DBS for refractory epilepsy performed a computer-based test of executive functions while DBS was repeatedly switched ON and OFF at MD and at the control location (ANT). In comparison to stimulation of the control location, when MD was stimulated, participants committed 2.26 times more errors in general (total errors; OR = 2.26, 95% CI [1.69, 3.01]) and 2.86 times more working memory-related errors specifically (incorrect button presses; OR = 2.88, CI [1.95, 4.24]). Similarly, participants committed 1.81 more errors in general ( OR = 1.81, CI [1.45, 2.24]) and 2.08 times more working memory-related errors ( OR = 2.08, CI [1.57, 2.75]) in comparison to no stimulation condition. "Total errors" is a composite score consisting of basic error types and was mostly driven by working memory-related errors. The facts that MD and a control location, ANT, are only few millimeters away from each other and that their stimulation produces very different results highlight the location-specific effect of DBS rather than regionally unspecific general effect. In conclusion, disrupting and recovering MD's function with high-frequency electric stimulation modulated participants' online working memory performance providing causal, in vivo evidence from humans for the role of MD in human working memory.

Vagus nerve stimulation improves working memory performance.

Vagus nerve stimulation (VNS) is used for treating refractory epilepsy and major depression. While the impact of this treatment on seizures has been established, its impact on human cognition remains equivocal. The goal of this study is to elucidate the immediate effects of vagus nerve stimulation on attention, cognition, and emotional reactivity in patients with epilepsy. Twenty patients (12 male and 8 female; 45 ± 13 years old) treated with VNS due to refractory epilepsy participated in the study. Subjects performed a computer-based test of executive functions embedded with emotional distractors while their brain activity was recorded with electroencephalography. Subjects' cognitive performance, early visual event-related potential N1, and frontal alpha asymmetry were studied when cyclic vagus nerve stimulation was on and when it was off. We found that vagus nerve stimulation improved working memory performance as seen in reduced errors on a subtask that relied on working memory, odds ratio (OR) = 0.63 (95% confidence interval, CI [0.47, 0.85]) and increased N1 amplitude, F(1, 15) = 10.17, p = .006. In addition, vagus nerve stimulation resulted in longer reaction time, F(1, 16) = 8.23, p = .019, and greater frontal alpha asymmetry, F(1, 16) = 11.79, p = .003, in response to threat-related distractors. This is the first study to show immediate improvement in working memory performance in humans with clinically relevant vagus nerve stimulation. Furthermore, vagus nerve stimulation had immediate effects on emotional reactivity evidenced in behavior and brain physiology.

Greater Attention to Task-Relevant Threat Due to Orbitofrontal Lesion.

Injury to the orbitofrontal cortex (OFC) is a frequent consequence of head injury and may lead to dysfunctional regulation of emotional and social behavior. Dysfunctional emotional behavior may partly be related to the role of the OFC in emotion-attention interaction, as reported previously. In order to better understand its role in emotion-attention and emotion-cognitive control interactions, we investigated attention allocation to task-relevant and task-irrelevant threat-related emotional stimuli during a task requiring cognitive control in patients with lesion to the OFC. We measured the behavioral performance and event-related potentials (ERP) of 13 patients with OFC lesion and 11 control subjects during a Go/NoGo visual discrimination task. In the task, line drawings of threatening (spider) and neutral (flower) figures served as either task-relevant Go or NoGo signals, or as task-irrelevant distractors. Overall performance did not differ between the groups. In contrast to the control group performance, the orbitofrontal group performance was improved by relevant threat signal in comparison with neutral signal. Further, task-relevant threat signals evoked larger frontocentral N2-P3 amplitude in the orbitofrontal group. Taken together, behavioral and electrophysiological results suggest that patients with OFC injury allocated more attentional and cognitive control resources in the context of task-relevant emotional stimuli. This study provides new evidence for the role of the OFC in emotion-attention and emotion-cognitive control interactions. Further, the OFC seems to contribute to the balance between voluntary and involuntary attention networks in context of emotional stimuli. Better understanding of alterations in emotion-attention interaction offers insight into affective dysfunction due to OFC lesion.

Human Brain Reacts to Transcranial Extraocular Light.

Transcranial extraocular light affects the brains of birds and modulates their seasonal changes in physiology and behavior. However, whether the human brain is sensitive to extraocular light is unknown. To test whether extraocular light has any effect on human brain functioning, we measured brain electrophysiology of 18 young healthy subjects using event-related potentials while they performed a visual attention task embedded with emotional distractors. Extraocular light delivered via ear canals abolished normal emotional modulation of attention related brain responses. With no extraocular light delivered, emotional distractors reduced centro-parietal P300 amplitude compared to neutral distractors. This phenomenon disappeared with extraocular light delivery. Extraocular light delivered through the ear canals was shown to penetrate at the base of the scull of a cadaver. Thus, we have shown that extraocular light impacts human brain functioning calling for further research on the mechanisms of action of light on the human brain.

Low attentional engagement makes attention network activity susceptible to emotional interference.

The aim of this study was to investigate whether emotion-attention interaction depends on attentional engagement. To investigate emotional modulation of attention network activation, we used a functional MRI paradigm consisting of a visuospatial attention task with either frequent (high-engagement) or infrequent (low-engagement) targets and intermittent emotional or neutral distractors. The attention task recruited a bilateral frontoparietal network with no emotional interference on network activation when the attentional engagement was high. In contrast, when the attentional engagement was low, the unpleasant stimuli interfered with the activation of the frontoparietal attention network, especially in the right hemisphere. This study provides novel evidence for low attentional engagement making attention control network activation susceptible to emotional interference.

Immediate effects of deep brain stimulation of anterior thalamic nuclei on executive functions and emotion-attention interaction in humans.

BACKGROUND: Deep brain stimulation (DBS) of anterior thalamic nuclei (ANT) is a novel promising therapeutic method for treating refractory epilepsy. Despite reports of subjective memory impairments and mood disturbances in patients with ANT-DBS, little is known of its effects on cognitive and affective processes. HYPOTHESIS: The anterior thalamus has connections to prefrontal and limbic networks important for cognitive control and emotional reactivity. More specifically, anterior cingulate cortex (ACC), linked with ANT, has been assigned roles related to response inhibition and attention allocation to threat. Thus, we hypothesized ANT-DBS to influence executive functions, particularly response inhibition, and modulate emotional reactivity to threat. METHOD: Twelve patients having undergone ANT-DBS for intractable epilepsy participated in the study. Patients performed a computer-based executive reaction time (RT) test--that is, a go/no-go visual discrimination task with threat-related emotional distractors and rule switching, while the DBS was switched ON (5/5 mA constant current) and OFF every few minutes. RESULTS: ANT-DBS increased the amount of commission errors--that is, errors where subjects failed to withhold from responding. Furthermore, ANT-DBS slowed RTs in context of threat-related distractors. When stimulation was turned off, threat-related distractors had no distinct effect on RTs. CONCLUSION: We found immediate objective effects of ANT-DBS on human cognitive control and emotion-attention interaction. We suggest that ANT-DBS compromised response inhibition and enhanced attention allocation to threat due to altered functioning of neural networks that involve the DBS-target, ANT, and the regions connected to it such as ACC. The results highlight the need to consider affective and cognitive side-effects in addition to the therapeutic effect when adjusting stimulation parameters. Furthermore, this study introduces a novel window into cognitive and affective processes by modulating the associative and limbic networks with direct stimulation of key nodes in the thalamus.

Threat interferes with response inhibition.

A potential threat, such as a spider, captures attention and engages executive functions to adjust ongoing behavior and avoid danger. We and many others have reported slowed responses to neutral targets in the context of emotional distractors. This behavioral slowing has been explained in the framework of attentional competition for limited resources with emotional stimuli prioritized. Alternatively, slowed performance could reflect the activation of avoidance/freezing-type motor behaviors associated with threat. Although the interaction of attention and emotion has been widely studied, little is known on the interaction between emotion and executive functions. We studied how threat-related stimuli (spiders) interact with executive performance and whether the interaction profile fits with a resource competition model or avoidance/freezing-type motor behaviors. Twenty-one young healthy individuals performed a Go-NoGo visual discrimination reaction time (RT) task engaging several executive functions with threat-related and emotionally neutral distractors. The threat-related distractors had no effect on the RT or the error rate in the Go trials. The NoGo error rate, reflecting failure in response inhibition, increased significantly because of threat-related distractors in contrast to neutral distractors, P less than 0.05. Thus, threat-related distractors temporarily impaired response inhibition. Threat-related distractors associated with increased commission errors and no effect on RT does not suggest engagement of avoidance/freezing-type motor behaviors. The results fit in the framework of the resource competition model. A potential threat calls for evaluation of affective significance as well as inhibition of undue emotional reactivity. We suggest that these functions tax executive resources and may render other executive functions, such as response inhibition, temporarily compromised when the demands for resources exceed availability.

Orbitofrontal cortex biases attention to emotional events.

We examined the role of orbitofrontal (OF) cortex in regulating emotion-attention interaction and the balance between involuntary and voluntary attention allocation. We studied patients with OF lesion applying reaction time (RT) and event-related potential (ERP) measures in a lateralized visual discrimination task with novel task-irrelevant affective pictures (unpleasant, pleasant, or neutral) preceding a neutral target. This allowed for comparing the effects of automatic attention allocation to emotional versus neutral stimuli on subsequent voluntary attention allocation to target stimuli. N2-P3a and N2-P3b ERP components served as measures of involuntary and voluntary attention allocation correspondingly. Enhanced N2-P3a amplitudes to emotional distractors and reduced N2-P3b amplitudes to targets preceded by emotional distractors were observed in healthy subjects, suggesting automatic emotional orienting interfered with subsequent voluntary orienting. OF patients showed an opposite pattern with tendency towards reduced N2-P3a responses to emotional distractors, suggesting impaired automatic orienting to emotional stimuli due to orbitofrontal damage. Enhanced N2-P3b responses to targets preceded by any affective distractor were observed in OF patients, suggesting bias towards voluntary target-related attention allocation due to orbitofrontal lesion. Behavioral evidence indicated that left visual field (LVF) attention performance was modulated by emotional stimuli. Specifically, OF patients responded faster to LVF targets subsequent to pleasant emotional distractors. We suggest that damage to the orbitofrontal circuitry leads to dysbalance between voluntary and involuntary attention allocation in the context of affective distractors with predisposition to posterior target-related processing over frontal novelty and affect-related processing. Furthermore, we suggest that orbitofrontal influence on emotion-attention interaction is valence and hemisphere dependent.

Persistent symptoms in mild to moderate traumatic brain injury associated with executive dysfunction.

In order to improve detection of subtle cognitive dysfunction and to shed light on the etiology of persistent symptoms after mild-to-moderate traumatic brain injury (TBI), we employed an experimental executive reaction time (RT) test, standardized neuropsychological tests, and diffusion tensor imaging (DTI). The Executive RT-Test, an Executive Composite Score from standardized neuropsychological tests, and DTI-indices in the midbrain differentiated between patients with persistent symptoms from those fully recovered after mild-to-moderate TBI. We suggest that persistent symptoms in mild-to-moderate TBI may reflect disrupted fronto-striatal network involved in executive functioning, and the Executive RT-Test provides an objective and novel method to detect it.

Trees over forest: unpleasant stimuli compete for attention with global features.

Whether emotional distracters call for attentional resources has been discussed in several studies. We have earlier shown that brief unpleasant distracters captured right hemisphere (RH) attentional resources as evidenced with reduced event-related potential responses and increased reaction times to nonemotional left visual field/RH targets. The aim of this study was to investigate whether emotional distracters selectively interfere with processes predominantly relying on the RH such as processing global visual features. Evoked potentials were recorded from 18 participants carrying out a visual discrimination task engaging global RH and local left hemisphere-dependent processes. Unpleasant distracters reduced global target detection-related right parietal activity. We conclude that brief unpleasant distracters compete for RH attentional resources with global level processing.

Emotionally arousing stimuli compete for attention with left hemispace.

Rapid interaction of the emotional and attentional networks is critical for adaptive behavior. Here, we examined the effects of emotional stimulation on hemifield attention allocation using event-related potential and behavioral measures. Participants performed a visual-discrimination task on nonemotional targets presented randomly in the left or right hemifield. A brief task-irrelevant emotional (pleasant or unpleasant; 150-ms duration) or neutral picture was presented centrally 350 ms before the next target (150-ms duration). Unpleasant stimuli interfered with the left visual field attention capacity, slowing behavioral responses to attended left field stimuli. In keeping with the behavioral data, event-related potential responses to nonemotional attended left field stimuli were reduced over the right parietal regions when preceded by an unpleasant event. The results provide electrophysiological and behavioral evidence that unpleasant, emotionally arousing stimuli interfere with the right hemisphere-dependent attention capacity.