Alpha modulation during working memory encoding predicts neurocognitive impairment in ADHD.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with working memory (WM) deficits. However, WM is a multiprocess construct that can be impaired through several pathways, leaving the source of WM impairments in ADHD unresolved. In this study, we aim to replicate, in an independent sample, previously reported deficits in component processes of WM deficits in ADHD and expand to consider their implications for neurocognitive outcomes. METHODS: In 119 children (7-14 years old, 85 with ADHD), we used electroencephalography measures to quantify component processes during performance of a spatial working memory task. We quantified stimulus encoding using alpha range (8-12 Hz) power; vigilance by the P2 event-related potential to cues; and WMmaintenance by occipital-alpha and frontal-theta (4-7 Hz) power. These measures were evaluated against metrics of executive function, ADHD symptoms, and academic achievement. RESULTS: Encoding alpha-power decreases and cue P2 amplitude were attenuated in ADHD, whereas occipital-alpha power during maintenance was significantly greater in ADHD, consistent with a compensatory response to weak encoding. Weak alpha modulation during encoding was associated with poorer reading comprehension and executive function, as well as enhanced ADHD symptoms. Previously reported effects in frontal-theta power failed to replicate. CONCLUSIONS: Stimulus encoding, a component process of WM coupled to alpha modulation, is impaired in ADHD, and, unlike WM maintenance or vigilance processes, has implications outside of the laboratory via a relationship with executive function, and, to a weaker extent, reading comprehension.

Effects of gender and executive function on visuospatial working memory in adult obsessive-compulsive disorder.

Visuospatial working memory (VSWM) is the ability of the brain to transiently store and manipulate visual information. VSWM deficiencies have been reported in obsessive-compulsive disorder (OCD), but not consistently, perhaps due to variability in task design and clinical patient factors. To explore this variability, this study assessed effects of the design factors task difficulty and executive organizational strategy and of the clinical factors gender, OCD symptom dimension, and duration of illness on VSWM in OCD. The CANTAB spatial working memory, spatial recognition memory, delayed matching to sample, and stop signal tasks were administered to 42 adult OCD patients and 42 age- and sex-matched healthy controls. Aims were to detect a possible VSWM deficit in the OCD sample, to evaluate influences of the above task and patient factors, to determine the specificity of the deficit to the visuospatial subdomain, and to examine effects of sustained attention as potential neurocognitive confound. We confirmed previous findings of a VSWM deficit in OCD that was more severe for greater memory load (task difficulty) and that was affected by task strategy (executive function). We failed to demonstrate significant deficits in neighboring or confounding neurocognitive subdomains (visual object recognition or visual object short-term memory, sustained attention). Notably, the VSWM deficit was only significant for female patients, adding to evidence for sexual dimorphism in OCD. Again as in prior work, more severe OCD symptoms in the symmetry dimension (but no other dimension) significantly negatively impacted VSWM. Duration of illness had no significant effect on VSWM. VSWM deficits in OCD appear more severe with higher task load and may be mediated through poor task strategy. Such deficits may present mainly in female patients and in (male and female) patients with symmetry symptoms.

Evaluating effect of symptoms heterogeneity on decision-making ability in obsessive-compulsive disorder.

AIMS: Despite having a univocal definition, obsessive-compulsive disorder (OCD) shows a remarkably phenotypic heterogeneity. The published reports show impaired decision-making in OCD patients, using tasks such as the Iowa Gambling Task (IGT). We wanted to verify the hypothesis of an IGT worse performance in a large sample of OCD patients and healthy control (HC) subjects and to examine the relation between neuropsychological performance in IGT and the OCD symptoms heterogeneity. METHODS: Binary data from the Yale-Brown Obsessive Compulsive Scale collected on a large sample of OCD patients were analyzed using a multidimensional item response theory model to explore the underlying structure of data, thus revealing latent factors. Factor scores were categorized into quartiles. Then, for each factor, we identified patients respectively with the highest versus lowest score. We evaluated whether symptom dimensions affect the probability of a correct answer over time generalized, during IGT performance, fitting a generalized linear mixed model. RESULTS: We found a general deficit in ambiguous decision-making in OCD compared to HC. Moreover, our findings suggested that OCD symptoms heterogeneity affects decision-making learning abilities during IGT. In fact, while 'Symmetry' and 'Washing' patients showed a learning curve during the task, other subgroups did not. CONCLUSIONS: Our study confirmed previous findings suggesting that OCD is characterized by a deficit in decision-making under uncertainty. Moreover, our study gave evidence about biological specificity for each symptom dimension in OCD. Data were discussed in the context of the somatic marker hypothesis, which was hypothesized to be reduced in OCD patients.

Trigeminal Nerve Stimulation for Attention-Deficit/Hyperactivity Disorder: Cognitive and Electroencephalographic Predictors of Treatment Response.

OBJECTIVE: The current study applies a precision medicine approach to trigeminal nerve simulation (TNS), a Food and Drug Administration-approved neuromodulation treatment for attention-deficit/hyperactivity disorder (ADHD), by testing secondary outcomes of cognitive and electroencephalographic [EEG] predictors of treatment response among subjects from the original randomized controlled trial. METHOD: Children aged 8 to 12 years with ADHD, were randomized to 4 weeks of active or sham TNS treatment, after which the sham group crossed over into 4 weeks of open-label treatment. TNS treatment responders (RESP) had an ADHD Rating Scale (ADHD-RS) Total score reduction of ≥25%, whereas nonresponders (NR) had <25% reduction posttreatment. Assessments included weekly behavioral ratings and pre-/posttreatment cognitive EEG measures. RESULTS: The final sample was 25 RESP and 26 NR comprising 34 male and 17 female children, with a mean (SD) age of 10.3 (1.4) years. Baseline measures that significantly differentiated RESP from NR included: lower working memory, lower spelling and mathematics achievement, deficits on behavioral ratings of executive function (BRIEF), and lower resting state EEG power in the right frontal (F4) region (all p values <.05). Compared to NRs, responders showed significantly increased right frontal EEG power with TNS treatment, which was predictive of improved executive functions and ADHD symptomatology (ß = 0.65, p < .001). When EEG findings and behavior were modeled together, the area under the curve (AUC) for BRIEF Working Memory scale was 0.83 (p = .003), indicating moderate prediction of treatment response. CONCLUSION: Children with ADHD who have executive dysfunction are more likely to be TNS responders and show modulation of right frontal brain activity, improved/normalized executive functions, and ADHD symptom reduction. CLINICAL TRIAL REGISTRATION INFORMATION: Developmental Pilot Study of External Trigeminal Nerve Stimulation for ADHD; http://clinicaltrials.gov; NCT02155608.

Event-related potentials to rare visual targets and negative symptom severity in a transdiagnostic psychiatric sample.

OBJECTIVES: Negative psychiatric symptoms are often resistant to treatments, regardless of the disorder in which they appear. One model for a cause of negative symptoms is impairment in higher-order cognition. The current study examined how particular bottom-up and top-down mechanisms of selective attention relate to severity of negative symptoms across a transdiagnostic psychiatric sample. METHODS: The sample consisted of 130 participants: 25 schizophrenia-spectrum disorders, 26 bipolar disorders, 18 unipolar depression, and 61 nonpsychiatric controls. The relationships between attentional event-related potentials following rare visual targets (i.e., N1, N2b, P2a, and P3b) and severity of the negative symptom domains of anhedonia, avolition, and blunted affect were evaluated using frequentist and Bayesian analyses. RESULTS: P3b and N2b mean amplitudes were inversely related to the Positive and Negative Syndrome Scale-Negative Symptom Factor severity score across the entire sample. Subsequent regression analyses showed a significant negative transdiagnostic relationship between P3b amplitude and blunted affect severity. CONCLUSIONS: Results indicate that negative symptoms, and particularly blunted affect, may have a stronger association with deficits in top-down mechanisms of selective attention. SIGNIFICANCE: This suggests that people with greater severity of blunted affect, independent of diagnosis, do not allocate sufficient cognitive resources when engaging in activities requiring selective attention.

Shared and unique neural mechanisms underlying pediatric trichotillomania and obsessive compulsive disorder.

BACKGROUND: Little is known about the neural underpinnings of pediatric trichotillomania (TTM). We examined error-related negativity (ERN)-amplitude and theta-EEG power differences among youth with TTM, OCD, and healthy controls (HC). METHODS: Forty channel EEG was recorded from 63 pediatric participants (22 with TTM, 22 with OCD, and 19 HC) during the Eriksen Flanker Task. EEG data from inhibitory control were used to derive estimates of ERN amplitude and event-related spectral power associated with motor inhibition. RESULTS: TTM and HC were similar in brain activity patterns in frontal and central regions and TTM and OCD were similar in the parietal region. Frontal ERN-amplitude was significantly larger in OCD relative to TTM and HC, who did not differ from each other. The TTM group had higher theta power compared to OCD in frontal and central regions, and higher theta than both comparison groups in right motor cortex and superior parietal regions. Within TTM, flanker task performance was correlated with EEG activity in frontal, central, and motor cortices whereas global functioning and impairment were associated with EEG power in bilateral motor and parietal cortices. CONCLUSIONS: Findings are discussed in terms of shared and unique neural mechanisms in TTM and OCD and treatment implications.

Neurochemical correlates of behavioral treatment of pediatric trichotillomania.

BACKGROUND: Trichotillomania (TTM) is a chronic and impairing psychiatric disorder with suspected dysfunctional cortico-striato-thalamo-cortical (CSTC) circuit activity reflecting excitatory/inhibitory signaling imbalance. TTM neurochemistry is understudied, with no prior research using magnetic resonance spectroscopy (MRS). This pilot investigation examined associations between TTM diagnosis, symptom severity, and response to behavioral treatment with MRS neurometabolites glutamate (Glu) and γ-aminobutyric acid (GABA) in CSTC structures. METHODS: Proton echo-planar spectroscopic imaging (PEPSI) MRS was acquired from bilateral pregenual anterior cingulate cortex (pACC), caudate, putamen, globus pallidus, thalamus, and proximal white matter in 10 unmedicated girls with TTM, ages 9-17 years, before and after treatment, and from 13 age- and sex-matched healthy controls. RESULTS: Nine of 10 TTM patients were treatment responders. Pretreatment mean Glu and GABA did not differ significantly between participants and controls. Pretreatment TTM symptoms were correlated with Glu in (left + right) pACC (r = 0.88, p = 0.02) and thalamus (r = 0.82, p = 0.012), and were negatively correlated with pACC GABA (r = -0.84, p = 0.034). Mean GABA in putamen increased 69% (baseline to post-treatment) (p = 0.027). Higher pretreatment Glu in caudate, putamen, globus pallidus, and thalamus predicted greater symptom decreases with treatment (all r < -0.6, p < 0.05); higher caudate GABA predicted less treatment-related symptom decline (r = 0.86, p = 0.014). LIMITATIONS: Small sample, GABA quantified with spectral fitting rather than editing. CONCLUSION: Consistent with other neuroimaging, MRS reveals discrete CSTC chemical changes with effective behavior therapy, and possibly with TTM etiology. TTM symptoms relate to excess excitatory versus inhibitory signaling in pACC and thalamus; symptom improvement may reflect reduced excitatory drive of the CSTC direct-pathway activity.

The role of avoidance motivation in the relationship between reward sensitivity and depression symptoms in adolescents: An ERP study.

Blunted neural responses to reward in an EEG paradigm (RewP) are associated with vulnerability to depression, but the pathways linking this biomarker to depressive symptoms are unclear. We examined whether the relationship between reward response (RewP mean amplitude and latency) and depression was in part explained by approach-motivated behaviors in adolescents with varying levels of depression. EEG was collected during a game rigged to provide win/loss trials. Longer RewP latency was associated with depression symptoms only when scores on a measure of avoidance motivation were included. These results suggest that treatments targeting avoidance may decrease vulnerability to depressive episodes.

Neural activation and connectivity during cued eye blinks in Chronic Tic Disorders.

OBJECTIVE: The pathophysiology of Chronic Tic Disorders (CTDs), including Tourette Syndrome, remains poorly understood. The goal of this study was to compare neural activity and connectivity during a voluntary movement (VM) paradigm that involved cued eye blinks among children with and without CTDs. Using the precise temporal resolution of electroencephalography (EEG), we used the timing and location of cortical source resolved spectral power activation and connectivity to map component processes such as visual attention, cue detection, blink regulation and response monitoring. We hypothesized that neural activation and connectivity during the cued eye blink paradigm would be significantly different in regions typically associated with effortful control of eye blinks, such as frontal, premotor, parietal, and occipital cortices between children with and without CTD. METHOD: Participants were 40 children (23 with CTD, 17 age-matched Healthy Control [HC]), between the ages of 8-12 (mean age = 9.5) years old. All participants underwent phenotypic assessment including diagnostic interviews, behavior rating scales and 128-channel EEG recording. Upon presentation of a cue every 3 s, children were instructed to make an exaggerated blink. RESULTS: Behaviorally, the groups did not differ in blink number, latency, or ERP amplitude. Within source resolved clusters located in left dorsolateral prefrontal cortex, posterior cingulate, and supplemental motor area, children with CTD exhibited higher gamma band spectral power relative to controls. In addition, significant diagnostic group differences in theta, alpha, and beta band power in inferior parietal cortex emerged. Spectral power differences were significantly associated with clinical characteristics such as tic severity and premonitory urge strength. After calculating dipole density for 76 anatomical regions, the CTD and HC groups had 70% overlap of top regions with the highest dipole density, suggesting that similar cortical networks were used across groups to carry out the VM. The CTD group exhibited significant information flow increase and dysregulation relative to the HC group, particularly from occipital to frontal regions. CONCLUSION: Children with CTD exhibit abnormally high levels of neural activation and dysregulated connectivity among networks used for regulation and effortful control of voluntary eye blinks.

Double-Blind, Sham-Controlled, Pilot Study of Trigeminal Nerve Stimulation for Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Trigeminal nerve stimulation (TNS), a minimal-risk noninvasive neuromodulation method, showed potential benefits for attention-deficit/hyperactivity disorder (ADHD) in an unblinded open study. The present blinded sham-controlled trial was conducted to assess the efficacy and safety of TNS for ADHD and potential changes in brain spectral power using resting-state quantitative electroencephalography. METHOD: Sixty-two children 8 to 12 years old, with full-scale IQ of at least 85 and Schedule for Affective Disorders and Schizophrenia-diagnosed ADHD, were randomized to 4 weeks of nightly treatment with active or sham TNS, followed by 1 week without intervention. Assessments included weekly clinician-administered ADHD Rating Scales (ADHD-RS) and Clinical Global Impression (CGI) scales and quantitative electroencephalography at baseline and week 4. RESULTS: ADHD-RS total scores showed significant group-by-time interactions (F1,228 = 8.12, p = .005; week 4 Cohen d = 0.5). CGI-Improvement scores also favored active treatment (χ21,168 = 8.75, p = .003; number needed to treat = 3). Resting-state quantitative electroencephalography showed increased spectral power in the right frontal and frontal midline frequency bands with active TNS. Neither group had clinically meaningful adverse events. CONCLUSION: This study demonstrates TNS efficacy for ADHD in a blinded sham-controlled trial, with estimated treatment effect size similar to non-stimulants. TNS is well tolerated and has minimal risk. Additional research should examine treatment response durability and potential impact on brain development with sustained use. CLINICAL TRIAL REGISTRATION INFORMATION: Trigeminal Nerve Stimulation for ADHD; http://clinicaltrials.gov/; NCT02155608.

Is distress tolerance an approach behavior? An examination of frontal alpha asymmetry and distress tolerance in adolescents.

Frontal EEG asymmetry, relatively greater left-than-right frontal activity (rLFA), has been associated with mood symptoms and approach versus withdrawal behaviors. Distress tolerance (DT), a transdiagnostic behavior, has yet to be examined as an approach behavior using rLFA. Adolescents (N = 20; M age = 14.53, SD = 2.09) completed a frustrating mirror-tracing task which provided an index of DT. Higher resting rLFA was associated with lower DT. The results are the first to identify a relationship between cortical activation and distress tolerance in adolescents. rLFA appears to be a neurophysiological index of behaviors associated with approach motivation and escape from punishment or aversive situations.

Frontal alpha asymmetry predicts inhibitory processing in youth with attention deficit/hyperactivity disorder.

INTRODUCTION: Atypical asymmetry in brain activity has been implicated in the behavioral and attentional dysregulation observed in ADHD. Specifically, asymmetry in neural activity in the right versus left frontal regions has been linked to ADHD, as well as to symptoms often associated with ADHD such as heightened approach behaviors, impulsivity and difficulties with inhibition. Clarifying the role of frontal asymmetry in ADHD-like traits, such as disinhibition, may provide information on the neurophysiological processes underlying these behaviors. METHOD: ADHD youth (ADHD: n = 25) and healthy, typically developing controls (TD: n = 25) underwent an electroencephalography (EEG) recording while completing a go/no-go task-a commonly used test measuring behavioral inhibition. In addition, advanced signal processing for source localization estimated the location of signal generators underlying frontal alpha asymmetry (FA) during correct and incorrect trials. RESULTS: This is the first study in ADHD to demonstrate that the dorsal-lateral prefrontal cortex (DLPFC) may be responsible for generating frontal alpha. During failed inhibition trials, ADHD youth displayed greater FA than TD youth. In addition, within the ADHD group, frontal asymmetry during later processing stages (i.e., 400-800ms after stimulus) predicted a higher number of commission errors throughout the task. CONCLUSIONS: These results suggest that frontal alpha asymmetry may be a specific biomarker of cognitive disinhibition among youth with ADHD.

Cingulate and thalamic metabolites in obsessive-compulsive disorder.

Focal brain metabolic effects detected by proton magnetic resonance spectroscopy (MRS) in obsessive-compulsive disorder (OCD) represent prospective indices of clinical status and guides to treatment design. Sampling bilateral pregenual anterior cingulate cortex (pACC), anterior middle cingulate cortex (aMCC), and thalamus in 40 adult patients and 16 healthy controls, we examined relationships of the neurometabolites glutamate+glutamine (Glx), creatine+phosphocreatine (Cr), and choline-compounds (Cho) with OCD diagnosis and multiple symptom types. The latter included OC core symptoms (Yale-Brown Obsessive-Compulsive Scale - YBOCS), depressive symptoms (Montgomery-Åsberg Depression Rating Scale - MADRS), and general functioning (Global Assessment Scale - GAS). pACC Glx was 9.7% higher in patients than controls. Within patients, Cr and Cho correlated negatively with YBOCS and MADRS, while Cr correlated positively with the GAS. In aMCC, Cr and Cho correlated negatively with MADRS, while Cr in thalamus correlated positively with GAS. These findings present moderate support for glutamatergic and cingulocentric perspectives on OCD. Based on our prior metabolic model of OCD, we offer one possible interpretation of these group and correlational effects as consequences of a corticothalamic state of elevated glutamatergic receptor activity alongside below-normal glutamatergic transporter activity.