Phase-Transitions in Disgust During Self-Initiated Eating Among Adolescents With Anorexia Nervosa and Related Low-Weight Eating Disorders and Matched Controls.

BACKGROUND: Understanding the emotional context of feeding behavior may help identify causal mechanisms of food avoidance among individuals with anorexia nervosa. Although predominant food avoidance models assume fear of fat drives feeding behavior, disgust may be more theoretically and proximally relevant to moment-to-moment experiences of feeding. This study, therefore, aimed to examine affect and food avoidance using automated affect analysis from facial response by measuring time-specific transitions in disgust during a laboratory eating paradigm. We hypothesized that phase transitions in disgust would distinguish temporally self-initiated eating from food avoidance. METHODS: Sixty-three adolescents with anorexia nervosa or another low-weight eating disorder (LWED) and 27 age- and sex-matched controls were recruited as part of a larger study; 45 patients and 22 controls provided data on autonomous eating and facial affect during a laboratory meal. Dynamic structural equation models quantified moment-to-moment relationships between disgust and feeding behavior. RESULTS: Self-initiated eating was associated with greater increases in disgust, but not fear, intensity among those with LWED relative to control participants and greater disgust intensity predicted lower likelihood of self-initiated eating. DISCUSSION: Phasic transitions in disgust provide moment-to-moment evidence of affective influence on self-initiated eating and lend credibility to the hypothesis that disgust contributes to food avoidance and initiation in individuals with LWED.

Training in Cognitive Reappraisal Normalizes Whole-Brain Indices of Emotion Regulation in Borderline Personality Disorder.

BACKGROUND: Borderline personality disorder (BPD) is the prototypical disorder of emotion dysregulation. We have previously shown that patients with BPD are impaired in their capacity to engage cognitive reappraisal, a frequently employed adaptive emotion regulation strategy. METHODS: Here, we report on the efficacy of longitudinal training in cognitive reappraisal to enhance emotion regulation in patients with BPD. Specifically, the training targeted psychological distancing, a reappraisal tactic whereby negative stimuli are viewed dispassionately as though experienced by an objective, impartial observer. At each of 5 sessions over 2 weeks, 22 participants with BPD (14 female) and 22 healthy control participants (13 female) received training in psychological distancing and then completed a widely used picture-based reappraisal task. Self-reported negative affect ratings and functional magnetic resonance imaging data were acquired at the first and fifth sessions. In addition to behavioral analyses, we performed whole-brain pattern expression analyses using independently defined patterns for negative affect and cognitive reappraisal implementation for each session. RESULTS: Patients with BPD showed a decrease in negative affect pattern expression following reappraisal training, reflecting a normalization in neural activity. However, they did not show significant change in behavioral self-reports. CONCLUSIONS: To our knowledge, this study represents the first longitudinal functional magnetic resonance imaging examination of task-based cognitive reappraisal training. Using a brief, proof-of-concept design, the results suggest a potential role for reappraisal training in the treatment of patients with BPD.

Distinct Topological Properties of the Reward Anticipation Network in Preadolescent Children With Binge Eating Disorder Symptoms.

OBJECTIVE: Few studies have considered the neural underpinnings of binge eating disorder (BED) in children, despite clinical and subclinical symptom presentation occurring in this age group. Symptom presentation at this age is of clinical relevance, as early onset of binge eating is linked to negative health outcomes. Studies in adults have highlighted dysfunction in the frontostriatal reward system as a potential candidate for binge eating pathophysiology, although the exact nature of such dysfunction is currently unclear. METHOD: Data from 83 children (mean age 9.9 years, SD = 0.60) with symptoms of BED (57% girls) and 123 control participants (mean age 10.0 years, SD = 0.60) (52% girls) were acquired from the 4.0 baseline release of the Adolescent Brain Cognitive Development Study. Task-based graph theoretic techniques were used to analyze data from anticipation trials of the monetary incentive delay task. Network and nodal properties were compared between groups. RESULTS: The BED-S group showed alterations in topological properties associated with the frontostriatal subnetwork, such as reduced nodal efficiency in the superior frontal gyrus, nucleus accumbens, putamen, and in normal sex-difference patterns of these properties, such as diminished girls-greater-than-boys pattern of betweenness-centrality in nucleus accumbens observed in controls. CONCLUSION: Distinct network properties and sex-difference patterns in preadolescent children with BED-S suggest dysregulation in the reward system compared to those of matched controls. For the first time, these results quantify this dysregulation in terms of systems-level properties during anticipation of monetary reward and significantly inform the early and sex-related brain markers of BED symptoms.

Outcomes of 11 dogs with short radius syndrome treated with acute arthroscopically assisted ulnar shortening.

OBJECTIVE: To describe the short-term outcome of acute arthroscopically assisted ulnar shortening (AUS), to treat short radius syndrome in dogs. STUDY DESIGN: Case series. ANIMALS: Eleven client owned dogs. METHODS: Records of dogs that had undergone AUS for treatment of short radius syndrome were reviewed for inclusion. Reporting data included among others pre- and postoperative radioulnar, humeroradial and humeroulnar distances, lameness scores, surgical times, complications and clinical outcome. RESULTS: Following AUS, radiohumeral articulation was improved in all dogs. Median presurgery radioulnar, humeroradial and humeroulnar values were 4.5, 3.2, and 2.2 mm and were improved with surgery by a median of 3.2, 1.8, and 1.2 mm, respectively. Median surgery time was 140 min. Median time to bone healing was 8 weeks (range: 4-14). Median time to last follow-up was 9 weeks (4-468). Median lameness score (scale 0-4) improved from 2 to 1. No major complications were reported. Short-term clinical outcome was graded by the surgeons as full function in four cases and acceptable function in seven. CONCLUSION AND CLINICAL RELEVANCE: Radiographic and arthroscopic radiohumeral articulation were improved and short-term clinical improvement was documented following AUS in all 11 dogs.

Effects of Stimulant Treatment on Changes in Brain Activation During Reward Notifications in Drug Naïve Youth With ADHD.

BACKGROUND: Research examining the potential effects of stimulant exposure in childhood on subsequent development of substance use disorder (SUD) have focused on differences in the brain reward system as a function of risk. METHODS: 18 drug naïve children ages 7 to 12 years (11 High Risk [ADHD + ODD/CD]; 7 Low Risk [ADHD only]), underwent fMRI scans before and after treatment with mixed amphetamine salts, extended release (MAS-XR). We examined correlations between clinical ratings and fMRI activation at baseline and following treatment as a function of risk status. RESULTS: High Risk children had higher activation than Low Risk children at baseline during both the Reward and Surprising Non-Reward conditions. Treatment produced strong differential effects on brain activation pertinent to group and reward outcome. CONCLUSIONS: Findings support the hypothesized role of reward mechanisms in SUD risk, and suggest that stimulant treatment may have differential effects on reward processing in relation to SUD risk.

Neurobiological basis of reinforcement-based decision making in adults with ADHD treated with lisdexamfetamine dimesylate: Preliminary findings and implications for mechanisms influencing clinical improvement.

BACKGROUND: ADHD is often described as a disorder of altered reward sensitivity, yet few studies have examined the extent to which: (i) treatments for ADHD impact reward-related mechanisms; and (ii) changes in the reward system are associated with clinical improvement. This study addresses these issues - examining the extent to which clinical improvement following lisdexamfetamine (LDX) treatment is associated with changes in brain reward system activation. METHODS: Twenty adults (M = 11, 55%, F = 9, 45%), ages 19-52 (M = 33.9, SD = 10.0) with ADHD participated in a randomized cross-over study with lisdexamfetamine (LDX) and placebo (PB). Changes in brain activation were assessed during functional magnetic resonance (fMRI) scans: after receiving 3-5 weeks of treatment with LDX and 3-5 weeks of no drug/PB. fMRI contrasts were derived from the passive-avoidance (PA) learning task, which assessed reward-related learning using computational variables. We analyzed the following conditions: the Choice-Phase, modulated by the expected value (EV; i.e., object-choose and object-reject), and the Feedback-Phase, modulated by the prediction error (PE; i.e., reward and punish). Clinical symptom severity was assessed via interview with the ADHD-Rating Scale (ADHD-RS-IV). To address the primary objective, we performed group-level mass-univariate regression analyses between LDX and PB of percent change of the ADHD-RS total scores and the four contrast images under the Choice- and Feedback-conditions. Significance was set at a whole-brain voxel-wise threshold of p < 0.05 with family-wise error (FWE) correction and an extent (cluster) threshold of 50 contiguous voxels. RESULTS: Improvement in ADHD symptoms with LDX was accompanied by significantly increased activation in a series of brain regions previously implicated in reinforcement processing in the choice and feedback conditions (e.g., left caudate and putamen, right orbitofrontal cortex, left middle frontal, superior frontal, and precentral gyri). CONCLUSIONS: These findings, while preliminary, are the first to show that ADHD symptom improvement with stimulant treatment is associated with increased responsiveness of brain systems engaged in reward processing. Results support the hypothesis that LDX treatment may restore balance to dysfunction (e.g., hypoactivation) within the brain reward circuitry in adults with ADHD. Trial RegistrationClinicaltrials.gov Identifier: NCT01924429.

Development and initial pilot validation of a treatment fidelity instrument for family-based interoceptive exposure for adolescents with low-weight eating disorders.

BACKGROUND: This pilot study outlines the development and psychometric evaluation of a therapist adherence coding measure for a novel treatment, Family-Based Treatment Interoceptive Exposure (FBT-IE). METHODS: The IE Adherence Coding Framework (IE-ACF) was developed from the FBT-IE Manual using an iterative process. Items on the IE-ACF were coded by two independent coders as either present or absent with therapists considered adherent if both independent coders coded the item as "present." Videotaped sessions of FBT-IE of 30 adolescents with low-weight eating disorders (DSM-5 typical/atypical anorexia nervosa) and their families were coded. Participants received the FBT-IE intervention as part of a randomized controlled trial. RESULTS: Seventy FBT-IE videos were coded. The IE-ACF identified a mean (SD) rating of 80% (±5%) therapist adherence to the protocol across the six-session treatment, with a per item adherence ranging from 36-100%. Two independent coders demonstrated moderate to almost perfect inter-rater reliability (κ range 0.78-0.96) across the sessions. CONCLUSION: IE-ACF measured therapist adherence to our novel FBT-IE treatment for adolescents with low-weight eating disorders. Through this study, we demonstrated that 1) our therapists were adherent to the FBT-IE manual in the context of an ongoing clinical trial and 2) that independent coders reliably coded sessions using our novel IE-ACF.

The nature of coxofemoral joint pathology across family Canidae.

We evaluated coxofemoral joints from museum specimens of: Vulpes lagopus; Vulpes vulpes; Vulpes velox; Nyctereutes procyonoides; Urocyon cinereoargenteus; Aenocyon [Canis] dirus; Canis latrans; Canis lupus lupus; Canis lupus familiaris; C. l. familiaris × latrans; and Canis dingo. Acetabular components included: fossa; articular surface; medial and lateral articular margins; and periarticular surfaces. Acetabular components variably revealed: osteophyte-like features; varying appearance of articular margin rims (especially contour changes); rough bone surfaces (especially fossa and articular surface); and surface wear. Proximal femoral components included: articular surface; articular margin; periarticular surfaces; and joint capsule attachment. Femoral components variably revealed: rough bone surface; bone loss; articular margin osteophyte-like features; caudal post-developmental mineralized prominence; and enthesophytes along the joint capsule attachment. Non-metric multidimensional scaling was used to analyze right-left asymmetric relationships between observed traits, across taxa. Significantly different acetabular trait asymmetry involved only C. latrans-C. l. familiaris; V. vulpes-N. procyonoides, and U. cinereoargenteus-N. procyonoides. There were no significant lateralized differences in proximal femoral traits involving modern canids, ancient and modern C. l. familiaris, or modern vulpines. Thus, the observations were strongly bilateral. We hypothesized high similarity of traits across taxa. The data confirm the hypothesis and strongly suggest broad and deep morphological and mechanistic conservation that almost certainly pre-existed (at least) all modern canids. Further zoological studies are needed to evaluate phylogenic implications in greater detail.

Activation of the cognitive control network associated with information uncertainty.

The cognitive control network (CCN) that comprises regions of the frontoparietal network, the cingulo-opercular network, and other sub-cortical regions as core structures is commonly activated by events with an increase in information uncertainty. However, it is not clear whether this CCN activation is associated with both information entropy that represents the information conveyed by the context formed by a sequence of events and the surprise that quantifies the information conveyed by a specific type of event in the context. We manipulated entropy and surprise in this functional magnetic resonance imaging study by varying the probability of occurrence of two types of events in both the visual and auditory modalities and measured brain response as a function of entropy and surprise. We found that activation in regions of the CCN increased as a function of entropy and surprise in both the visual and auditory tasks. The frontoparietal network and additional structures in the CCN mediated the relationship between these information measures and behavioral response. These results suggest that the CCN is a high-level modality-general neural entity for the control of the processing of information conveyed by both context and event.

Temporal Dynamics of Functional Brain States Underlie Cognitive Performance.

The functional organization of the human brain adapts dynamically in response to a rapidly changing environment. However, the relation of these rapid changes in functional organization to cognitive functioning is not well understood. This study used a graph-based time-frame modularity analysis approach to identify temporally recurrent functional configuration patterns in neural responses to an n-back working memory task during fMRI. Working memory load was manipulated to investigate the functional relevance of the identified brain states. Four distinct brain states were defined by the predominant patterns of activation in the task-positive, default-mode, sensorimotor, and visual networks. Associated with escalating working memory load, the occurrence of the task-positive state and the probability of transitioning into this state increased. In contrast, the occurrence of the default-mode and sensorimotor states and the probability of these 2 states transitioning away from the task-positive state decreased. The task-positive state occurrence rate and the probability of transitioning from the default-mode state back to the task-positive state explained a significant and unique portion of the variance in task performance. The results demonstrate that dynamic brain activities support successful cognitive functioning and may have heuristic value for understanding abnormal cognitive functioning associated with multiple neuropsychiatric disorders.

Supramodal Mechanisms of the Cognitive Control Network in Uncertainty Processing.

Information processing under conditions of uncertainty requires the involvement of cognitive control. Despite behavioral evidence of the supramodal function (i.e., independent of sensory modality) of cognitive control, the underlying neural mechanism needs to be directly tested. This study used functional magnetic imaging together with visual and auditory perceptual decision-making tasks to examine brain activation as a function of uncertainty in the two stimulus modalities. The results revealed a monotonic increase in activation in the cortical regions of the cognitive control network (CCN) as a function of uncertainty in the visual and auditory modalities. The intrinsic connectivity between the CCN and sensory regions was similar for the visual and auditory modalities. Furthermore, multivariate patterns of activation in the CCN predicted the level of uncertainty within and across stimulus modalities. These findings suggest that the CCN implements cognitive control by processing uncertainty as abstract information independent of stimulus modality.

Features of the Femoral Proximocaudal Joint Capsule Insertion Among Canids.

This observational study was conducted to evaluate the anatomic relationship between the proximocaudal femoral joint capsule insertion and the femoral caudolateral curvilinear osteophyte (CCO), across ancient and modern domestic and non-domestic canids. Museum specimens of proximal femora were screened for presence of remnant enthesophytes of the caudal joint capsule insertion (first inclusion criterion) and then for the CCO (second inclusion criterion). The initially screened population included 267 dry bone specimens: Six Canis species, hybrid coyote × domestic dog, and five vulpines (three Vulpes species, one Urocyon, and one Nyctereutes). Proximocaudal joint capsule insertion remnant enthesophytes were limiting at n = 19 specimens: Seven ancient domestic dogs, four modern coyotes, two ancient coyotes, two modern hybrid coyote × dog, two modern red foxes, and two modern raccoon dogs. The joint capsule enthesophytes are associated with inflammation, but are observed far less frequently than the CCO. The CCO is seen radiographically but is visible more frequently by direct inspection. The primary inclusion criterion necessarily was a visible caudal joint capsule insertion; spatial relationships of the CCO can be assigned with confidence only when a capsule insertion line can be recognized clearly. We demonstrate that the anatomic CCO associates with the joint capsule insertion being nonspecific and species-independent. A joint capsule insertion-CCO spatial relationship across species is an important new observation, strongly indicating that both are pathological features. Our data indicate need for new research to characterize the canid coxofemoral joint and its overt and incipient pathology in a phylogenetic context. Anat Rec, 302:2164-2170, 2019. © 2019 American Association for Anatomy.

Reward Processing in Drug-Naive Youth with Various Levels of Risk for Substance Use Disorders: A Pilot Study.

Background: It has been hypothesized that attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUDs) share common neurobiological features. When abnormalities in the mesolimbic reward system are characteristic of children with ADHD, it is unclear whether youth at particularly elevated risk for SUD may exhibit any further disturbances. The objective of this pilot study is to examine possible neurobiological differences among youth with different levels of SUD risk before exposure to any abusable substances. Methods: We recruited 47 drug-naive children aged 8-13 divided into (1) Low Risk (LR)-ADHD only (n = 16); (2) High Risk (HR)-ADHD+familial SUD (n = 17); and (3) healthy controls (HC, n = 14) who underwent one functional magnetic resonance imaging scan while performing a hybrid task. We used the omnibus analysis of covariance model to assess for group differences in brain activation in regions linked to the brain reward and behavioral control systems. Results: Behavioral analysis showed significant Cue and Flanker main effects, but no significant main effect for Group. Whole-brain analysis showed significant differences in widely distributed networks related to both reward processing and behavioral control. Region of interest (ROI) activations showed that the HR group had the highest activation in the right putamen during both expected rewards and unexpected nonreward outcomes and in the anterior cingulate cortex (ACC) during unexpected nonreward outcomes, while LR and HC youth showed similarly low activation during these contrasts. Furthermore, the LR and HR groups showed lower activation than HC in the right ACC and the right caudate during flanker contrasts. Conclusions: These are the first preliminary results to demonstrate that the magnitude of activation during reward notification differs as a function of reward outcome in youth at high versus LR for SUD, such that youth at LR for SUD exhibit the highest activation for positive rewards, whereas those at HR for SUD exhibit the highest activation during negative rewards.

Clinical outcomes after common calcanean tendon rupture repair in dogs with a loop-suture tenorrhaphy technique and autogenous leukoreduced platelet-rich plasma.

OBJECTIVE: To report outcomes of dogs with common calcanean tendon (CCT) ruptures treated with a platelet-rich plasma (PRP) enhanced nonabsorbable loop-suture technique. STUDY DESIGN: Retrospective case series. ANIMALS: Client-owned dogs (n = 12). METHODS: Medical records (2015-2017) of dogs with CCT ruptures repaired with a loop-suture tenorrhaphy and autogenous leukoreduced PRP were reviewed for signalment, history, type of injury, treatment, and clinical follow-up. Outcomes were assessed by functional anatomic measurements and Canine Orthopedic Index (COI) scores transformed to percentages, with 100% representing no problems. RESULTS: Twelve tendons were treated. Two dogs had major complications that were successfully revised. Follow-up was available in 11 of 12 dogs, with a median time of 12 months (range, 4-36), including COI for 11 dogs and anatomic measurements for 6 dogs. Anatomic measurements did not differ between treated and normal contralateral limbs (midthigh muscle mass P > .99, cranial tibial muscle mass P = .37, CCT diameter P = .08, tibiotarsal joint angle P > .99). Owners scored function (COI) as 96.4% (range, 93.3%-97.8%) and quality of life as 94.6% (range, 92%-98.2%). CONCLUSION: Loop-suture tenorrhaphy with application of autogenous leukoreduced PRP at the repair site resulted in restoration of functional anatomic measurements, high COI, and client satisfaction. CLINICAL SIGNIFICANCE: Loop-suture tenorrhaphy with local application of autogenous leukoreduced PRP appears to offer an acceptable option to treat CCT injuries in dogs.

Distinct topological properties of cue-evoked attention processing network in persisters and remitters of childhood ADHD.

Attention deficit/hyperactivity disorder (ADHD) is a highly prevalent and impairing neurodevelopmental disorder that persists into adulthood in a sizeable portion of afflicted children. The persistence of ADHD elevates the risk for adverse outcomes that result in substantial individual and societal burden. The objective of this study is to assess neurobiological substrates associated with variability of clinical outcomes in childhood ADHD, which has considerable value for the development of novel interventions that target mechanisms associated with recovery. A total of 36 young adults who were diagnosed with ADHD combined-type during childhood and 33 group-matched controls were involved in the study. Adults with childhood ADHD were further divided into 17 persisters and 19 remitters based on DSM-5 criteria. Functional magnetic resonance imaging data during a cue-evoked attention task were collected from each subject. The cue-evoked attention processing network was constructed using graph theoretic techniques. Network properties, including global-, local-, and nodal-efficiency, and network hubs were computed. Group comparisons of the network properties were conducted. Significantly lower nodal efficiency in right inferior frontal gyrus and reduced left side frontal-parietal functional interactions were observed in both remitters and persisters relative to the controls. The ADHD persisters showed a unique pattern of significantly lower nodal efficiency in right middle frontal gyrus (MFG) and hyper-interactions between bilateral MFG. This study suggests that right MFG functional impairments may relate to inactive fronto-parietal functional interactions for sensory and cognitive information processing and symptom persistence in young adults with childhood ADHD.

Evidence of prefrontal hyperactivation to food-cue reversal learning in adolescents with anorexia nervosa.

Food avoidance in anorexia nervosa (AN) has been hypothesized to occur as a result of deficits in reversal learning and altered neuronal processing of food-cue relationships. Extant findings suggest that those with AN may rely on heightened recruitment of prefrontal regions during initial formation of food-cue learning and difficulty extinguishing these relationships may result from elevated insula activity. We tested this hypothesis by comparing behavioral and neuronal responses to food-cue acquisition and reversal between adolescents with AN and healthy controls. Compared to controls, acquisition of a food-cue association and its reversal were associated with elevated prefrontal activation in adolescents with AN. There were no significant differences between groups in insula activation and no behavioral differences in the ability to acquire or reverse the food-cue association. The results suggest that adolescents with AN recruit prefrontal regulatory networks to acquire and alter expectancies to food. This pattern of top-down prefrontal control suggests that clinical interventions that target changes in food-cue relationships and rely on cognitive control may be less effective. Interventions that alter behavior without reliance on this top-down control may have advantages with this population.

Development of a methodology to combine fMRI and EMG to measure emotional responses in patients with anorexia nervosa.

OBJECTIVE: Individuals with eating disorders are theorized to have basic impairments in affective appraisal and social-emotional processing that contribute to pathogenesis of the disease. We aimed to determine if facial electromyography could be used to discriminate between happy and disgust emotions during simultaneous acquisition of an fMRI BOLD sequence in efforts to establish a novel tool for investigating emotion-driven hypotheses about eating pathology. In line with standards for rigor and reproducibility, we provide detailed protocols and code to support each step of this project. METHOD: Sixteen adolescents with low-weight eating disorders viewed emotional faces (Happy or Disgust) and were asked to mimic their facial expression during simultaneous BOLD and EMG (Corrugator supercilli, Lavator lavii, Zygomaticus major) acquisition. Trials were repeated with the scanner off and again with scanner on (i.e., fatigue). RESULTS: The Levator and Zygomaticus activation patterns discriminated disgust and happy faces successfully. The pattern held between scanner on and off conditions, but muscle activation attenuated in the Fatigue condition, especially for the Zygomaticus. DISCUSSION: Simultaneous fMRI-EMG is a new tool capable of discriminating specific emotions based on muscle activation patterns and can be leveraged to answer emotion-driven hypotheses about clinical populations characterized by difficulty labeling or processing emotions.

Defining the Construct of Synthetic Androgen Intoxication: An Application of General Brain Arousal.

Synthetic androgens (i. e., anabolic-androgenic steroids) are the primary component to the majority of problematic appearance and performance enhancing drug (APED) use. Despite evidence that these substances are associated with increased risk for aggression, violence, body image disturbances, and polypharmacy and can develop a pattern of chronic use consistent with drug dependence, there are no formal definitions of androgen intoxication. Consequently, the purpose of this paper is to establish a testable theory of androgen intoxication. We present evidence and theorize that synthetic androgen intoxication can be defined by a pattern of poor self-regulation characterized by increased propensity for a range of behaviors (e.g., aggression, sex, drug seeking, exercise, etc.) via androgen mediated effects on general brain arousal. This theory posits that androgens reduce threshold for emotional reactivity, motor response, and alertness to sensory stimuli and disrupt inhibitory control over the behaviors associated with synthetic androgen use. These changes result from alteration to basic neurocircuitry that amplifies limbic activation and reduces top-down cortical control. The implications for this definition are to inform APED specific hypotheses about the behavioral and psychological effects of APED use and provide a basis for establishing clinical, legal, and public health guidelines to address the use and misuse of these substances.

Lisdexamfetamine Targets Amygdala Mechanisms That Bias Cognitive Control in Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Prefrontal-limbic circuits that form the neural architecture for emotion to influence behavior have been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD) and represent a potentially important target of medication treatment that has not been substantively evaluated. This study tested the effect of the psychostimulant prodrug lisdexamfetamine dimesylate on amygdala activation and connectivity during the emotional bias of response execution and inhibition. METHODS: Twenty-five adults with ADHD were scanned twice with event-related functional magnetic resonance imaging while performing an emotional go/no-go task after 3 to 4 weeks of lisdexamfetamine treatment and 3 weeks off medication in a randomized, counterbalanced, hybrid crossover design. Drug, trial type, and face emotion (happy, sad, or neutral) were included as within-subjects factors in repeated measures analyses of activation and connectivity. RESULTS: Lisdexamfetamine was associated with increased right amygdala activation and reduced psychophysiological interactions with the orbital aspect of the left inferior frontal gyrus specifically for responses to sad faces compared with placebo, but there was no effect on the accuracy of response execution or inhibition. The relative gain in right amygdala activation in response to sad faces for lisdexamfetamine was correlated with a reduction in symptoms of ADHD. CONCLUSIONS: Treatment with lisdexamfetamine potentiates affective encoding in amygdala, purportedly via catecholaminergic mechanisms, but functionally disconnects the amygdala from inferior frontal regions that encode behavioral significance-resulting in reduced emotional bias of cognitive control. Pinpointing the neurophysiologic underpinnings of therapeutic improvement with lisdexamfetamine represents a first step in developing targeted approaches to treatment of ADHD.

Striatal Activation Predicts Differential Therapeutic Responses to Methylphenidate and Atomoxetine.

OBJECTIVE: Methylphenidate has prominent effects in the dopamine-rich striatum that are absent for the selective norepinephrine transporter inhibitor atomoxetine. This study tested whether baseline striatal activation would predict differential response to the two medications in youth with attention-deficit/hyperactivity disorder (ADHD). METHOD: A total of 36 youth with ADHD performed a Go/No-Go test during functional magnetic resonance imaging at baseline and were treated with methylphenidate and atomoxetine using a randomized cross-over design. Whole-brain task-related activation was regressed on clinical response. RESULTS: Task-related activation in right caudate nucleus was predicted by an interaction of clinical responses to methylphenidate and atomoxetine (F1,30 = 17.00; p < .001). Elevated caudate activation was associated with robust improvement for methylphenidate and little improvement for atomoxetine. The rate of robust response was higher for methylphenidate than for atomoxetine in youth with high (94.4% vs. 38.8%; p = .003; number needed to treat = 2, 95% CI = 1.31-3.73) but not low (33.3% vs. 50.0%; p = .375) caudate activation. Furthermore, response to atomoxetine predicted motor cortex activation (F1,30 = 14.99; p < .001). CONCLUSION: Enhanced caudate activation for response inhibition may be a candidate biomarker of superior response to methylphenidate over atomoxetine in youth with ADHD, purportedly reflecting the dopaminergic effects of methylphenidate but not atomoxetine in the striatum, whereas motor cortex activation may predict response to atomoxetine. These data do not yet translate directly to the clinical setting, but the approach is potentially important for informing future research and illustrates that it may be possible to predict differential treatment response using a biomarker-driven approach. CLINICAL TRIAL REGISTRATION INFORMATION: Stimulant Versus Nonstimulant Medication for Attention Deficit Hyperactivity Disorder in Children; https://clinicaltrials.gov/; NCT00183391.