Is lack of goal-conflict-specific rhythmicity a biomarker for treatment resistance in generalised anxiety but not social anxiety or major depression?

BACKGROUND: Anxiety and depression cause major detriment to the patient, family, and society - particularly in treatment-resistant (TR) cases, which are highly prevalent. TR prevalence may be due to current diagnoses being based not on biological measures but on symptom lists that suffer from clinical subjectivity, variation in symptom presentation, and comorbidity. AIMS: Goal-conflict-specific rhythmicity (GCSR) measured using the Stop-Signal Task (SST) may provide the first neural biomarker for an anxiety process and disorder. This GCSR has been validated with selective drugs for anxiety. So, we proposed that GCSR could differ between TR and non-TR individuals and do so differently between those diagnoses normally sensitive to selective anxiolytics and those not. METHODS: We recorded electroencephalograms (EEG) from 20 TR participants (4 GAD, 5 SAD and 11 MDD) and 24 non-TR participants (4 GAD, 5 SAD and 15 Comorbid GAD/MDD (GMD)) while they performed the SST. RESULTS: There was significant positive GCSR in all groups except the GAD-TR group. GAD-TR lacked GCSR in the low-frequency range. However, TR had little effect in SAD or MDD/GMD populations with apparent increases not decreases. CONCLUSIONS: Overall, these results suggest that GAD may occur in two forms: one resulting from excessive GCSR and so being drug sensitive, and the other resulting from some other mechanism and so being TR. In SAD and MDD groups, heightened GCSR could be a consequence rather than the cause, driven by mechanisms that are normally more sensitive to non-selective panicolytic antidepressants.

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.

Ketamine for treatment-resistant major depressive disorder: Double-blind active-controlled crossover study.

BACKGROUND: The N-methyl-D-aspartate antagonist ketamine has rapid onset antidepressant activity in treatment-resistant depression (TRD). AIMS: To evaluate mood rating, safety and tolerability data from patients with TRD treated with ketamine and the psychoactive control fentanyl, as part of a larger study to explore EEG biomarkers associated with mood response. METHODS: We evaluated the efficacy and safety of intramuscular racemic ketamine in 25 patients with TRD, using a double-blind active-controlled randomized crossover design. Ketamine doses were 0.5 and 1 mg/kg, and the psychoactive control was fentanyl 50 mcg, given at weekly intervals. RESULTS/OUTCOMES: Within 1 h of ketamine dosing, patients reported reduced depression and anxiety ratings, which persisted for up to 7 days. A dose-response profile for ketamine was noted for dissociative side effects, adverse events and changes in blood pressure; however, changes in mood ratings were broadly similar for both ketamine doses. Overall, 14/25 patients (56%) were responders (⩾50% reduction at 24 h compared with baseline) for either ketamine dose for the Hospital Anxiety and Depression Scale (HADS), and 18/25 (72%) were responders for the HADS-anxiety scale. After fentanyl, only 1/25 (HADS-depression) and 3/25 (HADS-anxiety) were responders. Ketamine was generally safe and well tolerated in this population. CONCLUSIONS: Our findings add to the literature confirming ketamine's activity against depressive and anxiety symptoms in patients with TRD.

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).

Exploring approach motivation: Correlating self-report, frontal asymmetry, and performance in the Effort Expenditure for Rewards Task.

Frontal EEG asymmetry has been investigated as a physiological metric of approach motivation, with higher left frontal activity (LFA) suggested to reflect approach motivation. However, correlations between LFA and traditional metrics of approach motivation (e.g., scores from the behavioral inhibition system/behavioral approach system [BIS/BAS] survey) are inconsistent. It is also not clear how LFA correlates to approach motivation on an observable, behavioral level. Here, we tested correlations between BIS/BAS scores, LFA, and performance in the Effort Expenditure for Rewards Task (EEfRT). In our sample (n = 49), BIS/BAS results did not correlate to LFA values (resting or task states), and were also unrelated to EEfRT performance variables. We found evidence of significant and distinct correlations between LFA and EEfRT performance. Resting-state LFA positively correlated to effort expenditure on lower utility trials, where reward size and/or probability were suboptimal. Task-onset LFA captured in the first 5 min of the task was related to overall behavioral performance in the EEfRT. High task-onset LFA correlated to high trial completion rates, high-effort trial selection percentages, and overall monetary earnings. One interpretation of these initial findings is that resting-state LFA reflects approach tendencies to expend effort, but that this extends to suboptimal situations, whereas task-state LFA better reflects effortful approach toward high-utility goals. Given the relatively small sample size and the risk of Type I/II errors, we present the study as exploratory and the results as preliminary. However, the findings highlight interesting initial links between LFA and EEfRT performance. The need for larger replication studies is discussed.

Effects of ketamine in patients with treatment-refractory generalized anxiety and social anxiety disorders: Exploratory double-blind psychoactive-controlled replication study.

BACKGROUND: We previously reported that ketamine has anxiolytic effects in patients with treatment-resistant generalized anxiety and social anxiety disorders. AIMS: The purpose of this study was to replicate our earlier report about ketamine's anxiolytic activity, using a more robust study design. METHODS: This was a double-blind, psychoactive-controlled ascending dose study in 12 patients with treatment-resistant generalized anxiety and social anxiety disorders who were not currently depressed. Ascending doses of ketamine (0.25, 0.5, 1 mg/kg) were administered at weekly intervals, and midazolam 0.01 mg/kg, the control, was randomly inserted into the ketamine dose sequence. Assessments included ratings of anxiety and dissociation, safety and tolerability, and blood samples for ketamine pharmacokinetics and BDNF concentrations. RESULTS: Improvements in anxiety ratings occurred within an hour of ketamine dosing, and persisted for up to 1 week. A dose-response profile was noted for anxiolytic effects, dissociative side effects, and changes in blood pressure and heart rate after ketamine dosing. Midazolam had minor brief effects on anxiety ratings. Ketamine was safe and well tolerated. Ketamine pharmacokinetics were correlated with dissociation ratings. Serum BDNF concentrations declined over time and were similar for all treatments. CONCLUSIONS: Ketamine may be a potential therapeutic option for patients with treatment-resistant generalized anxiety and social anxiety disorders.

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.

Ketamine Effects on EEG during Therapy of Treatment-Resistant Generalized Anxiety and Social Anxiety.

BACKGROUND: Ketamine is swiftly effective in a range of neurotic disorders that are resistant to conventional antidepressant and anxiolytic drugs. The neural basis for its therapeutic action is unknown. Here we report the effects of ketamine on the EEG of patients with treatment-resistant generalized anxiety and social anxiety disorders. METHODS: Twelve patients with refractory DSM-IV generalized anxiety disorder and/or social anxiety disorder provided EEG during 10 minutes of relaxation before and 2 hours after receiving double-blind drug administration. Three ascending ketamine dose levels (0.25, 0.5, and 1 mg/kg) and midazolam (0.01 mg/kg) were given at 1-week intervals to each patient, with the midazolam counterbalanced in dosing position across patients. Anxiety was assessed pre- and postdose with the Fear Questionnaire and HAM-A. RESULTS: Ketamine dose-dependently improved Fear Questionnaire but not HAM-A scores, decreased EEG power most at low (delta) frequency, and increased it most at high (gamma) frequency. Only the decrease in medium-low (theta) frequency at right frontal sites predicted the effect of ketamine on the Fear Questionnaire. Ketamine produced no improvement in Higuchi's fractal dimension at any dose or systematic changes in frontal alpha asymmetry. CONCLUSIONS: Ketamine may achieve its effects on treatment-resistant generalized anxiety disorder and social anxiety disorder through related mechanisms to the common reduction by conventional anxiolytic drugs in right frontal theta. However, in the current study midazolam did not have such an effect, and it remains to be determined whether, unlike conventional anxiolytics, ketamine changes right frontal theta when it is effective in treatment-resistant depression.

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.