Midfrontal theta reactivity to conflict and error are linked to externalizing and internalizing respectively.

Dimensional psychopathology scores measure symptom severity; cutting across disorder categories. Their clinical utility is high given comorbidity, but their neural basis is unclear. We used scalp electroencephalography (EEG) to concurrently assess neural activity across internalizing and externalizing traits. "Theta rhythm" (4-7 Hz) spectral power at the frontal midline site Fz in specific goal conflict and action error phases within a trial of a Stop-Signal Task was extracted using process-specific contrasts. A final sample of 146 community participants (63 males, 83 females; mean age = 36; SD = 9; range = 18 - 56), oversampled for externalizing disorder (49% diagnosed with a DSM-5 externalizing disorder), also supplied psychopathology and personality data. We used the Minnesota Multiphasic Personality Inventory-3 (MMPI-3) to measure symptoms and traits of psychopathology. An MMPI-3 measure of the higher-order internalizing psychopathology spectrum was positively correlated with action error theta. An MMPI-3 measure of the higher-order spectrum of externalizing psychopathology was negatively correlated with goal-conflict theta. We showed that goal-conflict and error theta activity are higher-order processes that index psychopathology severity. The associations extend into the nominally healthy range, and so reflect theta-related factors that apply to the general population as well as patients with sub-threshold diagnoses.

Alpha wave asymmetry is associated with only one component of melancholia, and in different directions across brain regions.

Alpha wave asymmetry inconsistently correlates with Major Depressive Disorder (MDD). One possible reason for this inconsistency is the heterogeneity of MDD, leading to study of depressive 'subtypes', one of which is Melancholia. To investigate the correlation between Melancholia and alpha-wave asymmetry, 100 community participants (44 males, 56 females; aged at least 18 yr) completed the Zung self-rated Depression Scale, and underwent 3 min of eyes closed EEG recording from 24 scalp sites. There was no significant correlation between EEG data and Melancholia total score for the entire sample, but there was for those participants who had clinically significant depression (n = 33). When examined at the level of individual Melancholia scale items, significant EEG data correlations were found for some of the items but not for others. Factor analysis revealed a two-factor structure for the Melancholia scale, only one of which exhibited significant correlations with EEG AA data. Further exploration of those data identified two subcomponents of that Melancholia factor, one which was inversely correlated with frontal alpha asymmetry, and another which was directly correlated with parietal-occipital alpha wave asymmetry. These findings suggest that Melancholia may itself be heterogeneous, similarly to MDD, and rely upon different aspects of cognitive function.

Network analysis of frontal lobe alpha asymmetry confirms the neurophysiological basis of four subtypes of depressive behavior.

Introduction: Although depression is widespread carries a major disease burden, current treatments remain non-universally effective, arguably due to the heterogeneity of depression, and leading to the consideration of depressive "subtypes" or "depressive behavior subtypes." One such model of depressive behavior (DB) subtypes was investigated for its associations with frontal lobe asymmetry (FLA), using a different data analytic procedure than in previous research in this field. Methods: 100 community volunteers (54 males, 46 females) aged between 18 yr. and 75 years (M = 32.53 yr., SD = 14.13 yr) completed the Zung Self-rating Depression Scale (SDS) and underwent 15 min of eyes closed EEG resting data collection across 10 frontal lobe sites. DB subtypes were defined on the basis of previous research using the SDS, and alpha-wave (8-13 Hz) data produced an index of FLA. Data were examined via network analysis. Results: Several network analyses were conducted, producing two models of the association between DB subtypes and FLA, confirming unique neurophysiological profiles for each of the four DB subtypes. Discussion: As well as providing a firm basis for using these DB subtypes in clinical settings, these findings provide a reasonable explanation for the inconsistency in previous FLA-depression research.

EEG frontal lobe asymmetry as a function of sex, depression severity, and depression subtype.

To investigate possible contributors to the inconsistent association between frontal lobe asymmetry (FLA) and depression, EEG data were collected across five frontal sites, and examined for their associations with four subtypes of depression (Depressed mood, Anhedonia, Cognitive depression, Somatic depression). One hundred community volunteers (54 males, 46 females) aged at least 18 yr completed standardized scales for depression and anxiety, and gave EEG data under Eyes Open and Eyes Closed conditions. Results indicated that, although there was no significant correlation between the differences in EEG power across each of the five pairs of frontal sites and total depression scores, there were several meaningful correlations (accounting for at least 10% of the variance) between specific EEG site differences data and each of the four depression subtypes. There were also different patterns of association between FLA and the depression subtypes according to sex, and total depression severity. These findings help to explain the apparent inconsistency in previous FLA-depression results, and argue for a more nuanced approach to this hypothesis.

Right Frontal Theta: Is It a Response Biomarker for Ketamine's Therapeutic Action in Anxiety Disorders?

Anxiety disorders are the most prevalent mental disorders in the world, creating huge economic burdens on health systems and impairing the quality of life for those affected. Recently, ketamine has emerged as an effective anxiolytic even in cases resistant to conventional treatments (TR); but its therapeutic mechanism is unknown. Previous data suggest that ketamine anxiety therapy is mediated by reduced right frontal electroencephalogram (EEG) theta power measured during relaxation. Here we test for a similar theta reduction between population-sample, presumed treatment-sensitive, (TS) anxiety patients and healthy controls. Patients with TS DSM-5 anxiety disorder and healthy controls provided EEG during 10 min of relaxation and completed anxiety-related questionnaires. Frontal delta, theta, alpha1, alpha2, beta, and gamma power, Higuchi's fractal dimension (HFD) and frontal alpha asymmetry (FAA) values were extracted to match ketamine testing; and we predicted that the controls would have less theta power at F4, relative to the TS anxious patients, and no differences in HFD or FAA. We provide graphical comparisons of our frontal band power patient-control differences with previously published post-pre ketamine TR differences. As predicted, theta power at F4 was significantly lower in controls than patients and FAA was not significantly different. However, HFD was unexpectedly reduced at lateral sites. Gamma power did not increase between controls and patients suggesting that the increased gamma produced by ketamine relates to dissociation rather than therapy. Although preliminary, and indirect, our results suggest that the anxiolytic action of ketamine is mediated through reduced right frontal theta power.

Right frontal anxiolytic-sensitive EEG 'theta' rhythm in the stop-signal task is a theory-based anxiety disorder biomarker.

Psychiatric diagnoses currently rely on a patient's presenting symptoms or signs, lacking much-needed theory-based biomarkers. Our neuropsychological theory of anxiety, recently supported by human imaging, is founded on a longstanding, reliable, rodent 'theta' brain rhythm model of human clinical anxiolytic drug action. We have now developed a human scalp EEG homolog-goal-conflict-specific rhythmicity (GCSR), i.e., EEG rhythmicity specific to a balanced conflict between goals (e.g., approach-avoidance). Critically, GCSR is consistently reduced by different classes of anxiolytic drug and correlates with clinically-relevant trait anxiety scores (STAI-T). Here we show elevated GCSR in student volunteers divided, after testing, on their STAI-T scores into low, medium, and high (typical of clinical anxiety) groups. We then tested anxiety disorder patients (meeting diagnostic criteria) and similar controls recruited separately from the community. The patient group had higher average GCSR than their controls-with a mixture of high and low GCSR that varied with, but cut across, conventional disorder diagnosis. Consequently, GCSR scores should provide the first theoretically-based biomarker that could help diagnose, and so redefine, a psychiatric disorder.

Laterality of an EEG anxiety disorder biomarker largely follows handedness.

Anxiety disorders are the most common mental disorders impacting people worldwide. Using an auditory Stop Signal Task (SST), we have developed an anxiety disorder biomarker (goal-conflict specific rhythmicity/GCSR) that occurs at the right frontal site F8 in right-handed participants. Here, we compare its laterality in left-handers (n = 26) versus demographically-matched right-handers (n = 26) between the ages of 18-30. We assessed the effects on GCSR power of the handedness of the participants (left or right), blocks of the SST, left-right variation across frontal channels (F7, F3, Fz, F4, F8), and EEG frequency (4-12 Hz). Left-handers differed from right-handers most at the channels furthest from the midline. This difference was largely a mirroring of right hander responses by left handers. With frontal channels coded in reverse order for left handers the original significant differences disappeared. Some differences remained between the groups in the frequency variation across blocks of testing. These and other data suggest that the circuitry engaged by conflict in the SST is different from that directly controlling stopping behaviour. Our results also suggest that where GCSR is used as an anxiety process or disorder biomarker in groups that combine both left and right-handed people, data only from the channel ipsilateral to the dominant hand should be used (F7, or F8, respectively).

Anxiety process "theta" biomarker in the stop signal task eliminated by a preceding relaxation test.

Anxiety disorders are currently the most prevalent psychiatric diseases in Europe and the United States, the 6th highest cause of years of life lived with disability, and so a grave and ever-increasing burden on health care resources. Categorization of specific anxiety disorders is constantly evolving, but even the new Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) manual uses symptom lists, not objective biomarkers. The DSM-5 and International Classification of Diseases (10th ed.) also aim for single diagnoses, but patients present with mixed symptoms that fit multiple diagnoses. In 1 step toward a solution to this problem, we previously reported on a human electroencephalogram anxiety process biomarker, goal-conflict-specific rhythmicity (GCSR) in a stop signal task (SST). GCSR appears homologous with rodent rhythmical slow activity, 4-12 Hz "theta" rhythmicity that, in the rat hippocampus, predicts human clinical anxiolytic action with, so far, no false positives (even with sedatives) or negatives (even with drugs ineffective in panic or depression). However, within-task stability of GCSR is too variable for test-retest. Here we tested the stability of GCSR when a simple relaxation task preceded the SST. We found that prior exposure of participants (56 female, 39 male; mean age = 21.87 years; reporting no medical or psychological treatment or any type of emotional disorder in the last 12 months) to the relaxation task appeared to almost completely eliminate GCSR. We therefore conclude that, when elicited in the stop signal task, GCSR represents a labile emotional state and should be assessed alone or as the 1st test of a series. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Human anxiety-specific "theta" occurs with selective stopping and localizes to right inferior frontal gyrus.

Anxiety disorders have high prevalence and generate major disability. But they have poor treatment targeting because psychiatry lacks diagnostic biomarkers. Right frontal goal-conflict-specific-rhythmicity (GCSR) in the simple stop signal task appears homologous to hippocampal "theta" as an anxiety-process biomarker but is weak and transient. An anticipatory response inhibition task (ARIT) elicits strong subjective conflict and so might generate stronger GCSR. Healthy participants provided EEG during an ARIT, which allowed direct comparison of selective (left, SG; right, GS), and nonselective (both, SS) handed stopping. We assessed GCSR as intermediate versus the average of short and long delay stop-specific power. SG produced right frontal 5-12 Hz GCSR that, as in the SST: significantly correlated with trait anxiety and neuroticism; and was sensitive to pregabalin (75 mg), buspirone (10 mg), and perhaps triazolam (0.25 mg). GS and SS produced faster stopping and only 9-10Hz GCSR, which did not correlate significantly with trait anxiety or neuroticism and was sensitive to pregabalin and buspirone but not triazolam. Source localization suggested that GCSR, like stopping, involves multiple right frontal circuits that depend on response speed. Anxiolytic-sensitive GCSR generalizes from the speeded stop signal task to fixed-time anticipatory response inhibition tasks. GCSR, and the circuits engaged, vary with stop signal RTs conditions. Tasks with longer stop times may be optimal to generate GCSR homologous with rodent hippocampal theta as (a) the first direct anchor of a specific neural form of trait anxiety; (b) a single-dose screen in normal humans for novel anxiolytics; and (c) a potential clinical anxiety biomarker. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Higuchi's fractal dimension, but not frontal or posterior alpha asymmetry, predicts PID-5 anxiousness more than depressivity.

Depression is a major cause of health disability. EEG measures may provide one or more economical biomarkers for the diagnosis of depression. Here we compared frontal alpha asymmetry (FAA), posterior alpha asymmetry (PAA), and Higuchi's fractal dimension (HFD) for their capacity to predict PID-5 depressivity and for the specificity of these predictions relative to PID-5 anxiousness. University students provided 8 or 10 minutes of resting EEG and PID-5 depressivity and PID-5 anxiousness questionnaire scores. FAA and PAA had no significant correlations with the measures at any electrode pair. There were distinct frontal and posterior factors underlying HFD that correlated significantly with anxiousness and with each other. Posterior HFD also correlated significantly with depressivity, though this was weaker than the correlation with anxiousness. The portion of depressivity variance accounted for by posterior HFD was not unique but shared with anxiousness. Inclusion of anxiety disorder patients into the sample rendered the frontal factor somewhat more predictive than the posterior one but generally strengthened the prior conclusions. Contrary to our predictions, none of our measures specifically predicted depressivity. Previous reports of links with depression may involve confounds with concurrent anxiety. Indeed, HFD may be a better measure of anxiety than depression; and its previous linkage to depression may be due to a confound between the two, given the high incidence of depression in cases of severe anxiety.

Removing eye blink artefacts from EEG-A single-channel physiology-based method.

BACKGROUND: EEG signals are often contaminated with artefacts, particularly with large signals generated by eye blinks. Deletion of artefact can lose valuable data. Current methods of removing the eye blink component to leave residual EEG, such as blind source component removal, require multichannel recording, are computationally intensive, and can alter the original EEG signal. NEW METHOD: Here we describe a novel single-channel method using a model based on the ballistic physiological components of the eye blink. This removes the blink component, leaving uncontaminated EEG largely unchanged. Processing time allows its use in real-time applications such as neurofeedback training. RESULTS: Blink removal had a success rate of over 90% recovered variance of original EEG when removing synthesised eye blink components. Fronto-lateral sites were poorer (∼80%) than most other sites (92-96%), with poor fronto-polar results (67%). COMPARISONS WITH EXISTING METHODS: When compared with three popular independent component analysis (ICA) methods, our method was only slightly (1%) better at frontal midline sites but significantly (>20%) better at lateral sites with an overall advantage of ∼10%. CONCLUSIONS: With few recording channels and real-time processing, our method shows clear advantages over ICA for removing eye blinks. It should be particularly suited for use in portable brain-computer-interfaces and in neurofeedback training.

Testing an anxiety process biomarker: Generalisation from an auditory to a visual stimulus.

We have previously reported an anxiolytic-sensitive human EEG biomarker, goal conflict specific rhythmicity (GCSR), using an auditory stop signal task (SST). Here we test if a visual SST could allow testing of GCSR in people with hearing impairments. The visual SST produced GCSR within the 4-12Hz band at the expected right frontal site, F8, but to a lesser extent than in previous auditory SSTs, possibly due to response instability. Positive GCSR appeared to be reduced by both buspirone (10mg), and triazolam (0.25mg), as previously; negative GCSR was increased. However, neuroticism, trait anxiety and Behavioural Inhibition System scores failed to show consistent positive correlations with GCSR, contrary to prediction. The visual SST generates anxiolytic-sensitive GCSR; but its limited extent and unexpected personality correlations suggest it needs further development to obtain quantitative equivalence with the auditory SST.