Hypoactivation of ventromedial frontal cortex in major depressive disorder: an MEG study of the Reward Positivity.

Background: The Reward Positivity (RewP) is sensitive and specific electrophysiological marker of reward receipt. These characteristics make it a compelling candidate marker of dysfunctional reward processing in major depressive disorder. We previously proposed that the RewP is a nexus of multiple aspects of reward variance, and that a diminished RewP in depression might only reflect a deficit in some of this variance. Specifically, we predicted a diminished ventromedial contribution in depression in the context of maintained reward learning. Methods: Here we collected magnetoencephalographic (MEG) recordings of reward receipt in 43 individuals with major depressive disorder (MDD group) and 38 healthy controls (CTL group). MEG allows effective source estimation due to the absence of volume conduction that compromises electroencephalographic recordings. Results: The MEG RewP analogue was generated by a broad set of cortical areas, yet only right ventromedial and right ventral temporal areas were diminished in MDD. These areas correlated with a principal component of anhedonia derived from multiple questionnaires. Compellingly, BA25 was the frontal region with the largest representation in both of these effects. Conclusions: These findings not only advance our understanding underlying the computation of the RewP, but they also dovetail with convergent findings from other types of functional source imaging in depression, as well as from deep brain stimulation treatments. Together, these discoveries suggest that the RewP may be a valuable marker for objective assessment of reward affect and its disruption in major depression.

Slowing of Parameterized Resting-State Electroencephalography After Mild Traumatic Brain Injury.

Reported changes in electroencephalography (EEG)-derived spectral power after mild traumatic brain injury (mTBI) remains inconsistent across existing literature. However, this may be a result of previous analyses depending solely on observing spectral power within traditional canonical frequency bands rather than accounting for the aperiodic activity within the collected neural signal. Therefore, the aim of this study was to test for differences in rhythmic and arrhythmic time series across the brain, and in the cognitively relevant frontoparietal (FP) network, and observe whether those differences were associated with cognitive recovery post-mTBI. Resting-state electroencephalography (rs-EEG) was collected from 88 participants (56 mTBI and 32 age- and sex-matched healthy controls) within 14 days of injury for the mTBI participants. A battery of executive function (EF) tests was collected at the first session with follow-up metrics collected approximately 2 and 4 months after the initial visit. After spectral parameterization, a significant between-group difference in aperiodic-adjusted alpha center peak frequency within the FP network was observed, where a slowing of alpha peak frequency was found in the mTBI group in comparison to the healthy controls. This slowing of week 2 (collected within 2 weeks of injury) aperiodic-adjusted alpha center peak frequency within the FP network was associated with increased EF over time (evaluated using executive composite scores) post-mTBI. These findings suggest alpha center peak frequency within the FP network as a candidate prognostic marker of EF recovery and may inform clinical rehabilitative methods post-mTBI.

Amphetamine increases motivation of humans and mice as measured by breakpoint, but does not affect an Electroencephalographic biomarker.

Translation of drug targets from preclinical studies to clinical trials has been aided by cross-species behavioral tasks, but evidence for brain-based engagement during task performance is still required. Cross-species progressive ratio breakpoint tasks (PRBTs) measure motivation-related behavior and are pharmacologically and clinically sensitive. We recently advanced elevated parietal alpha power as a cross-species electroencephalographic (EEG) biomarker of PRBT engagement. Given that amphetamine increases breakpoint in mice, we tested its effects on breakpoint and parietal alpha power in both humans and mice. Twenty-three healthy participants performed the PRBT with EEG after amphetamine or placebo in a double-blind design. C57BL/6J mice were trained on PRBT with EEG (n = 24) and were treated with amphetamine or vehicle. A second cohort of mice was trained on PRBT without EEG (n = 40) and was treated with amphetamine or vehicle. In humans, amphetamine increased breakpoint. In mice, during concomitant EEG, 1 mg/kg of amphetamine significantly decreased breakpoint. In cohort 2, however, 0.3 mg/kg of amphetamine increased breakpoint consistent with human findings. Increased alpha power was observed in both species as they reached breakpoint, replicating previous findings. Amphetamine did not affect alpha power in either species. Amphetamine increased effort in humans and mice. Consistent with previous reports, elevated parietal alpha power was observed in humans and mice as they performed the PRBT. Amphetamine did not affect this EEG biomarker of effort. Hence, these findings support the pharmacological predictive validity of the PRBT to measure effort in humans and mice and suggest that this EEG biomarker is not directly reflective of amphetamine-induced changes in effort.

Medication-invariant resting aperiodic and periodic neural activity in Parkinson's disease.

Parkinson's disease (PD) has been associated with greater total power in canonical frequency bands (i.e., alpha, beta) of the resting electroencephalogram (EEG). However, PD has also been associated with a reduction in the proportion of total power across all frequency bands. This discrepancy may be explained by aperiodic activity (exponent and offset) present across all frequency bands. Here, we examined differences in the eyes-open (EO) and eyes-closed (EC) resting EEG of PD participants (N = 26) on and off medication, and age-matched healthy controls (CTL; N = 26). We extracted power from canonical frequency bands using traditional methods (total alpha and beta power) and extracted separate parameters for periodic (parameterized alpha and beta power) and aperiodic activity (exponent and offset). Cluster-based permutation tests over spatial and frequency dimensions indicated that total alpha and beta power, and aperiodic exponent and offset were greater in PD participants, independent of medication status. After removing the exponent and offset, greater alpha power in PD (vs. CTL) was only present in EO recordings and no reliable differences in beta power were observed. Differences between PD and CTL in the resting EEG are likely driven by aperiodic activity, suggestive of greater relative inhibitory neural activity and greater neuronal spiking. Our findings suggest that resting EEG activity in PD is characterized by medication-invariant differences in aperiodic activity which is independent of the increase in alpha power with EO. This highlights the importance of considering aperiodic activity contributions to the neural correlates of brain disorders.

Test-retest reliability of spectral parameterization by 1/f characterization using SpecParam.

SpecParam (formally known as FOOOF) allows for the refined measurements of electroencephalography periodic and aperiodic activity, and potentially provides a non-invasive measurement of excitation: inhibition balance. However, little is known about the psychometric properties of this technique. This is integral for understanding the usefulness of SpecParam as a tool to determine differences in measurements of cognitive function, and electroencephalography activity. We used intraclass correlation coefficients to examine the test-retest reliability of parameterized activity across three sessions (90 minutes apart and 30 days later) in 49 healthy young adults at rest with eyes open, eyes closed, and during three eyes closed cognitive tasks including subtraction (Math), music recall (Music), and episodic memory (Memory). Intraclass correlation coefficients were good for the aperiodic exponent and offset (intraclass correlation coefficients > 0.70) and parameterized periodic activity (intraclass correlation coefficients > 0.66 for alpha and beta power, central frequency, and bandwidth) across conditions. Across all three sessions, SpecParam performed poorly in eyes open (40% of participants had poor fits over non-central sites) and had poor test-retest reliability for parameterized periodic activity. SpecParam mostly provides reliable metrics of individual differences in parameterized neural activity. More work is needed to understand the suitability of eyes open resting data for parameterization using SpecParam.

Depth recordings of the mouse homologue of the Reward Positivity.

We recently advanced a rodent homologue for the reward-specific, event-related potential component observed in humans known as the Reward Positivity. We sought to determine the cortical source of this signal in mice to further test the nature of this homology. While similar reward-related cortical signals have been identified in rats, these recordings were all performed in cingulate gyrus. Given the value-dependent nature of this event, we hypothesized that more ventral prelimbic and infralimbic areas also contribute important variance to this signal. Depth probes assessed local field activity in 29 mice (15 males) while they completed multiple sessions of a probabilistic reinforcement learning task. Using a priori regions of interest, we demonstrated that the depth of recording in the cortical midline significantly correlated with the size of reward-evoked delta band spectral activity as well as the single trial correlation between delta power and reward prediction error. These findings provide important verification of the validity of this translational biomarker of reward responsiveness, learning, and valuation.

Affective imagery boosts the reward related delta power in hazardous drinkers.

The Reward Positivity (RewP) is an event-related potential component with a delta band spectral representation that is elicited by reward receipt. Evidence suggests that RewP is modulated by both reward probability as well as affective valuation ("liking"). Here we determined whether RewP is a marker of enhanced hedonic salience of alcohol images in hazardous drinkers. We recruited 54 participants (Hazardous Drinkers = 28, Control = 26) who completed a reinforcement learning task with affective versus alcohol imagery during feedback. The learning task used images of puppies vs. alcohol paired with reinforcing feedback. Both groups rated categories of affective images (puppies, scenery, babies, neutral) similarly, but the hazardous drinking group rated alcohol significantly higher. There were no group differences in performance or in RewP amplitudes, even as a function of alcohol imagery. Contrary to prior findings, we did not observe a significant correlation between alcohol image rating and alcohol-specific RewP amplitude, although we did observe this relationship with the alcohol-specific delta band spectral representation of RewP. Within hazardous drinking group, there was significant correlation between hazardous drinking (AUDIT score) and alcohol-specific RewP indicating an inter-individual influence of drinking habits on affect specific RewP. These findings suggest a domain-specific enhancement of reward responsiveness in hazardous drinkers.

Evoked mid-frontal activity predicts cognitive dysfunction in Parkinson's disease.

BACKGROUND: Cognitive dysfunction is a major feature of Parkinson's disease (PD), but the pathophysiology remains unknown. One potential mechanism is abnormal low-frequency cortical rhythms which engage cognitive functions and are deficient in PD. We tested the hypothesis that mid-frontal delta/theta rhythms predict cognitive dysfunction in PD. METHOD: We recruited 100 patients with PD and 49 demographically similar control participants who completed a series of cognitive control tasks, including the Simon, oddball and interval-timing tasks. We focused on cue-evoked delta (1-4 Hz) and theta (4-7 Hz) rhythms from a single mid-frontal EEG electrode (cranial vertex (Cz)) in patients with PD who were either cognitively normal, with mild-cognitive impairments (Parkinson's disease with mild-cognitive impairment) or had dementia (Parkinson's disease dementia). RESULTS: We found that PD-related cognitive dysfunction was associated with increased response latencies and decreased mid-frontal delta power across all tasks. Within patients with PD, the first principal component of evoked electroencephalography features from a single electrode (Cz) strongly correlated with clinical metrics such as the Montreal Cognitive Assessment score (r=0.34) and with National Institutes of Health Toolbox Executive Function score (r=0.46). CONCLUSIONS: These data demonstrate that cue-evoked mid-frontal delta/theta rhythms directly relate to cognition in PD. Our results provide insight into the nature of low-frequency frontal rhythms and suggest that PD-related cognitive dysfunction results from decreased delta/theta activity. These findings could facilitate the development of new biomarkers and targeted therapies for cognitive symptoms of PD.

Impaired cognitive control after moderate prenatal alcohol exposure corresponds to altered EEG power during a rodent touchscreen continuous performance task.

Although it is well established that alcohol consumption during pregnancy can lead to lifelong difficulties in offspring, Fetal Alcohol Spectrum Disorders (FASD) remain a common neurodevelopmental syndrome. Translational behavioral tools that target similar brain circuits across species can facilitate understanding of these cognitive consequences. Touchscreen behavioral tasks for rodents enable easy integration of dura recordings of electroencephalographic (EEG) activity in awake behaving animals, with clear translational generalizability. Recently, we showed that Prenatal Alcohol Exposure (PAE) impairs cognitive control on the touchscreen 5-Choice Continuous Performance Task (5C-CPT) which requires animals to touch on target trials (hit) and withhold responding on non-target trials (correct rejection). Here, we extended these findings to determine whether dura EEG recordings would detect task-relevant differences in medial prefrontal cortex (mPFC) and posterior parietal cortex (PPC) corresponding with behavioral alterations in PAE animals. Replicating previous findings, PAE mice made more false alarm responses versus controls and had a significantly lower sensitivity index. All mice, regardless of sex or treatment, demonstrated increased frontal theta-band power during correct trials that followed an error (similar to post-error monitoring commonly seen in human participants). All mice showed a significant decrease in parietal beta-band power when performing a correct rejection versus a hit. PAE mice of both sexes showed a significantly larger decrease in parietal beta-band power when successfully rejecting non-target stimuli. These findings suggest that moderate exposure to alcohol during development can have long lasting effects on cognitive control, and task-relevant neural signals may provide a biomarker of impaired function across species.

Heart rate variability may index emotion dysregulation in alcohol-related intimate partner violence.

Introduction: Intimate partner violence is a serious public health problem that costs the United States more than $4.1 billion in direct medical and mental health costs alone. Furthermore, alcohol use contributes to more frequent and more severe intimate partner violence incidents. Compounding this problem is treatments for intimate partner violence have largely been socially informed and demonstrate poor efficacy. We argue that improvements in intimate partner treatment will be gained through systematic scientific study of mechanisms through which alcohol is related to intimate partner violence. We hypothesize that poor emotional and behavioral regulation as indexed by the respiratory sinus arrythymia measure of heart rate variability is a key mechanism between alcohol use and intimate partner violence. Method: The present study is a placebo-controlled alcohol administration study with an emotion-regulation task that investigated heart rate variability in distressed violent and distressed nonviolent partners. Results: We found a main effect for alcohol on heart rate variability. We also found a four-way interaction whereby distressed violent partners exhibited significant reductions in heart rate variability when acutely intoxicated and attempting to not respond to their partners evocative stimuli. Discussion: These findings suggest that distressed violent partners may adopt maladaptive emotion regulation strategies such as rumination and suppression when intoxicated and attempting to not respond to partner conflict. Such strategies of emotion regulation have been shown to have many deleterious emotional, cognitive and social consequences for individuals who adopt them, possibly including intimate partner violence. These findings also highlight an important novel treatment target for intimate partner violence and suggest that novel treatments should focus on teaching effective conflict resolution and emotion-regulation strategies that may be augmented by biobehavioral treatments such as heart rate variability biofeedback.

Reduced positive affect alters reward learning via reduced information encoding in the Reward Positivity.

Reward Positivity (RewP) is a feedback-locked event-related potential component that is specifically elicited by rewarding feedback and scales with positive reward prediction error, a hallmark of reinforcement learning models. The RewP is also diminished in depression, suggesting that it may be a novel marker of anhedonia. Here, we examined if a sad mood induction offered an opportunity to causally induce a mood-related alteration of the RewP and reward-related learning. In Experiment 1 (N = 50 total), participants were randomly assigned to previously established sad or neutral mood induction procedures before a probabilistic selection task. This manipulation failed to induce changes in affect, suggesting that standard methods are inadequate. In Experiment 2 (N = 50 total), participants were randomly assigned to newly developed happy versus sad mood manipulations, which successfully induced large changes in affect. While the RewP was unaffected by mood induction, positive mood moderated the relationship between prediction error encoding in the RewP and reward learning, such that low positive mood and low prediction error encoding resulted in poorer reward learning. These findings provide a mechanistic example of how reduced positive affect moderates reward learning via poorer information encoding in the RewP.

Prefrontal transcranial magnetic stimulation boosts response vigour during reinforcement learning in healthy adults.

A 10-Hz repetitive transcranial magnetic stimulation to the left dorsal lateral prefrontal cortex has been shown to increase dopaminergic activity in the dorsal striatum, a region strongly implicated in reinforcement learning. However, the behavioural influence of this effect remains largely unknown. We tested the causal effects of 10-Hz stimulation on behavioural and computational characteristics of reinforcement learning. A total of 40 healthy individuals were randomized into active and sham (placebo) stimulation groups. Each participant underwent one stimulation session (1500 pulses) in which stimulation was applied over the left dorsal lateral prefrontal cortex using a robotic arm. Participants then completed a reinforcement learning task sensitive to striatal dopamine functioning. Participants' choices were modelled using a reinforcement learning model (Q-learning) that calculates separate learning rates associated with positive and negative reward prediction errors. Subjects receiving active stimulation exhibited increased reward rate (number of correct responses per second of task activity) compared with those in sham. Computationally, although no group differences were observed, the active group displayed a higher learning rate for correct trials (αG) compared with incorrect trials (αL). Finally, when tested with novel pairs of stimuli, the active group displayed extremely fast reaction times, and a trend towards a higher reward rate. This study provided specific behavioural and computational accounts of altered striatal-mediated behaviour, particularly response vigour, induced by a proposed increase of dopamine activity by 10-Hz stimulation to the left dorsal lateral prefrontal cortex. Together, these findings bolster the use of repetitive transcranial magnetic stimulation to target neurocognitive disturbances attributed to the dysregulation of dopaminergic-striatal circuits.

Electrophysiological Markers of Aberrant Cue-Specific Exploration in Hazardous Drinkers.

Background: Hazardous drinking is associated with maladaptive alcohol-related decision-making. Existing studies have often focused on how participants learn to exploit familiar cues based on prior reinforcement, but little is known about the mechanisms that drive hazardous drinkers to explore novel alcohol cues when their value is not known. Methods: We investigated exploration of novel alcohol and non-alcohol cues in hazardous drinkers (N = 27) and control participants (N = 26) during electroencephalography (EEG). A normative computational model with two free parameters was fit to estimate participants' weighting of the future value of exploration and immediate value of exploitation. Results: Hazardous drinkers demonstrated increased exploration of novel alcohol cues, and conversely, increased probability of exploiting familiar alternatives instead of exploring novel non-alcohol cues. The motivation to explore novel alcohol stimuli in hazardous drinkers was driven by an elevated relative future valuation of uncertain alcohol cues. P3a predicted more exploratory decision policies driven by an enhanced relative future valuation of novel alcohol cues. P3b did not predict choice behavior, but computational parameter estimates suggested that hazardous drinkers with enhanced P3b to alcohol cues were likely to learn to exploit their immediate expected value. Conclusions: Hazardous drinkers did not display atypical choice behavior, different P3a/P3b amplitudes, or computational estimates to novel non-alcohol cues-diverging from previous studies in addiction showing atypical generalized explore-exploit decisions with non-drug-related cues. These findings reveal that cue-specific neural computations may drive aberrant alcohol-related decision-making in hazardous drinkers-highlighting the importance of drug-relevant cues in studies of decision-making in addiction.

Novelty-induced frontal-STN networks in Parkinson's disease.

Novelty detection is a primitive subcomponent of cognitive control that can be deficient in Parkinson's disease (PD) patients. Here, we studied the corticostriatal mechanisms underlying novelty-response deficits. In participants with PD, we recorded from cortical circuits with scalp-based electroencephalography (EEG) and from subcortical circuits using intraoperative neurophysiology during surgeries for implantation of deep brain stimulation (DBS) electrodes. We report three major results. First, novel auditory stimuli triggered midfrontal low-frequency rhythms; of these, 1-4 Hz "delta" rhythms were linked to novelty-associated slowing, whereas 4-7 Hz "theta" rhythms were specifically attenuated in PD. Second, 32% of subthalamic nucleus (STN) neurons were response-modulated; nearly all (94%) of these were also modulated by novel stimuli. Third, response-modulated STN neurons were coherent with midfrontal 1-4 Hz activity. These findings link scalp-based measurements of neural activity with neuronal activity in the STN. Our results provide insight into midfrontal cognitive control mechanisms and how purported hyperdirect frontobasal ganglia circuits evaluate new information.

Cognitive control in Parkinson's disease.

Cognitive control is the ability to act according to plan. Problems with cognitive control are a primary symptom and a major decrement of quality of life in Parkinson's disease (PD). Individuals with PD have problems with seemingly different controlled processes (e.g., task switching, impulsivity, gait disturbance, apathetic motivation). We review how these varied processes all rely upon disease-related alteration of common neural substrates, particularly due to dopaminergic imbalance. A comprehensive understanding of the neural systems underlying cognitive control will hopefully lead to more concise and reliable explanations of distributed deficits. However, high levels of clinical heterogeneity and medication-invariant control deficiencies suggest the need for increasingly detailed elaboration of the neural systems underlying control in PD.

Amphetamine alters an EEG marker of reward processing in humans and mice.

The bench-to-bedside development of pro-cognitive therapeutics for psychiatric disorders has been mired by translational failures. This is, in part, due to the absence of pharmacologically sensitive cognitive biomarkers common to humans and rodents. Here, we describe a cross-species translational marker of reward processing that is sensitive to the aminergic agonist, d-amphetamine. Motivated by human electroencephalographic (EEG) findings, we recently reported that frontal midline delta-band power is an electrophysiological biomarker of reward surprise in humans and in mice. In the current series of experiments, we determined the impact of parametric doses of d-amphetamine on this reward-related EEG response from humans (n = 23) and mice (n = 28) performing a probabilistic learning task. In humans, d-amphetamine (placebo, 10 mg, 20 mg) boosted the Reward Positivity event-related potential (ERP) component as well as the spectral delta-band representations of this signal. In mice, d-amphetamine (placebo, 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg) boosted both reward and punishment ERP features, yet there was no modulation of spectral activities. In sum, the present results confirm the role of dopamine in the generation of the Reward Positivity in humans, and pave the way toward a pharmacologically valid biomarker of reward sensitivity across species.

EEG reveals that dextroamphetamine improves cognitive control through multiple processes in healthy participants.

The poor translatability between preclinical and clinical drug trials has limited pro-cognitive therapeutic development. Future pro-cognitive drug trials should use translatable cross-species cognitive tasks with biomarkers (1) relevant to specific cognitive constructs, and (2) sensitive to drug treatment. Here, we used a difficulty-modulated variant of a cross-species cognitive control task with simultaneous electroencephalography (EEG) to identify neurophysiological biomarkers sensitive to the pro-cognitive effects of dextroamphetamine (d-amp) (10 or 20 mg) in healthy adults (n = 23), in a randomized, placebo-controlled, counterbalanced, double blind, within-subject study, conducted across three test days each separated by one week. D-amp boosted d-prime, sped reaction time, and increased frontal P3a amplitude to non-target correct rejections independent of task difficulty. Task difficulty did however, moderate d-amp effects on EEG during target performance. D-amp suppressed frontal theta power during easy target responses which negatively correlated with drug-induced improvement in hit rate while d-amp-induced changes in P3b amplitude during hard target trials strongly correlated with drug-induced improvement in hit rate. In summary, d-amp affected both behavioral and neurophysiological measures of cognitive control elements. Under low-demand, d-amp diminished cognitive control by suppressing theta, yet under high-demand it boosted control in concert with higher P3b amplitudes. These findings thus appear to reflect a gain-sharpening effect of d-amp: during high-demand processes were boosted while during low-demand processes were neglected. Future studies will use these neurophysiological measures of cognitive control as biomarkers to predict d-amp sensitivity in people with cognitive control deficits, including schizophrenia.

The reward positivity is sensitive to affective liking.

The EEG feature known as the Reward Positivity (RewP) is elicited by reward receipt and appears to reflect sensitively and specifically positive prediction errors during reinforcement learning. Yet, the RewP also is modulated by state and trait affect, suggesting that it has a more complex computational role than simple reinforcement surprise. We conducted a series of experiments aimed to investigate underlying affect processing reflected in the RewP during a reinforcement learning task. In the first experiment (N = 25), we manipulated the type of rewards a person could win (simple points or hedonically-appraised pictures). Although there were no differences in the amplitudes of the RewP for different types of rewards, there was a significant correlation between the individual rating of liking for the images and RewP amplitude. In a second experiment (N = 25), we manipulated reinforcement rates (easy vs. hard) and affective picture content (liked vs. ambivalent) to examine the potential interaction of prediction error and liking on RewP amplitude. We again found a significant relationship between liking and RewP amplitude, however, only in the hard condition. These findings suggest that the RewP reflects cortical computations of reward surprise as well as hedonic liking, identifying it as a possible nexus where multidimensional value is computed.