Rebecca E. Hommer

Inhibitory Motor Control in Response Stopping and Response Switching

While much is known about the neural regions recruited in the human brain when a dominant motor response becomes inappropriate and must be stopped, less is known about the regions that support switching to a new, appropriate, response. Using functional magnetic resonance imaging with two variants of the stop-signal paradigm that require either stopping altogether or switching to a different response, we examined the brain systems involved in these two forms of executive control. Both stopping trials and switching trials showed common recruitment of the right inferior frontal gyrus, presupplementary motor area, and midbrain. Contrasting switching trials with stopping trials showed activation similar to that observed on response trials (where the initial response remains appropriate and no control is invoked), whereas there were no regions that showed significantly greater activity for stopping trials compared with switching trials. These results show that response switching can be supported by the same neural systems as response inhibition, and suggest that the same mechanism of rapid, nonselective response inhibition that is thought to support speeded response stopping can also support speeded response switching when paired with execution of the new, appropriate, response.

A Developmental Study of the Feedback-Related Negativity From 10–17 Years: Age and Sex Effects for Reward Versus Non-Reward

We employed event-related potentials to examine the feedback-related negativity (FRN), during a non-learning reward versus non-reward task. We compared 10–12-year-old, 13–14-year-old, and 15–17-year-old youth (n = 91). Age effects included a larger FRN for younger age groups, regardless of feedback type, and a decrease in peak latency for feedback, across age groups as a linear trend. Males showed larger responses irrespective of feedback type and longer latency for rewarded feedback. Source modeling revealed reward/non-reward differences in the anterior cingulate cortex (ACC) and orbitofrontal cortex, most strongly in the subgenual ACC. Males showed more subgenual ACC activity for feedback overall.

Neural correlates of stress and favorite‐food cue exposure in adolescents: A functional magnetic resonance imaging study

Adolescence is a critical period of neurodevelopment for stress and appetitive processing, as well as a time of increased vulnerability to stress and engagement in risky behaviors. This study was conducted to examine brain activation patterns during stress and favorite‐food‐cue experiences relative to a neutral‐relaxing condition in adolescents. Functional magnetic resonance imaging was employed using individualized script‐driven guided imagery to compare brain responses with such experiences in 43 adolescents. Main effects of condition and gender were found, without a significant gender‐by‐condition interaction. Stress imagery, relative to neutral, was associated with activation in the caudate, thalamus, left hippocampus/parahippocampal gyrus, midbrain, left superior/middle temporal gyrus, and right posterior cerebellum. Appetitive imagery of favorite food was associated with caudate, thalamus, and midbrain activation compared with the neutral‐relaxing condition. To understand neural correlates of anxiety and craving, subjective (self‐reported) measures of stress‐induced anxiety and favorite‐food‐cue‐induced craving were correlated with brain activity during stress and appetitive food‐cue conditions, respectively. High self‐reported stress‐induced anxiety was associated with hypoactivity in the striatum, thalamus, hippocampus, and midbrain. Self‐reported favorite‐food‐cue‐induced craving was associated with blunted activity in cortical‐striatal regions, including the right dorsal and ventral striatum, medial prefrontal cortex, motor cortex, and left anterior cingulate cortex. These findings in adolescents indicate the activation of predominantly subcortical‐striatal regions in the processing of stressful and appetitive experiences and link hypoactive striatal circuits to self‐reported stress‐induced anxiety and cue‐induced favorite‐food craving. Hum Brain Mapp 34:2561–2573, 2013.

Clinical Presentation of Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections in Research and Community Settings

BACKGROUND The first cases of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) were described >15 years ago. Since that time, the literature has been divided between studies that successfully demonstrate an etiologic relationship between Group A streptococcal (GAS) infections and childhood-onset obsessive-compulsive disorder (OCD), and those that fail to find an association. One possible explanation for the conflicting reports is that the diagnostic criteria proposed for PANDAS are not specific enough to describe a unique and homogeneous cohort of patients. To evaluate the validity of the PANDAS criteria, we compared clinical characteristics of PANDAS patients identified in two community practices with a sample of children meeting full research criteria for PANDAS. METHODS A systematic review of clinical records was used to identify the presence or absence of selected symptoms in children evaluated for PANDAS by physicians in Hinsdale, Illinois (n=52) and Bethesda, Maryland (n=40). RESULTS were compared against data from participants in National Institute of Mental Health (NIMH) research investigations of PANDAS (n=48). RESULTS As described in the original PANDAS cohort, males outnumbered females (95:45) by ∼ 2:1, and symptoms began in early childhood (7.3±2.7 years). Clinical presentations were remarkably similar across sites, with all children reporting acute onset of OCD symptoms and multiple comorbidities, including separation anxiety (86-92%), school issues (75-81%), sleep disruptions (71%), tics (60-65%), urinary symptoms (42-81%), and others. Twenty of the community cases (22%) failed to meet PANDAS criteria because of an absence of documentation of GAS infections. CONCLUSIONS The diagnostic criteria for PANDAS can be used by clinicians to accurately identify patients with common clinical features and shared etiology of symptoms. Although difficulties in documenting an association between GAS infection and symptom onset/exacerbations may preclude a diagnosis of PANDAS in some children with acute-onset OCD, they do appear to meet criteria for pediatric acute-onset neuropsychiatric syndrome (PANS).

Schizophrenia and Autism—Related Disorders

The clinical connections between schizophrenia (SCZ) and autism spectrum disorder (ASD) have long been recognized. More than a century ago, Bleuler ascribed 4 primary symptoms to the group of disorders he termed “schizophrenia”: autism (turning inward to oneself), ambivalence, affective disturbance, and loosening of associations.1 In 1933, Potter described childhood SCZ as including: (1) loss of interest in the environment; (2) dereistic thinking; (3) thought disturbance; (4) difficulties with emotional rapport; (5) decreased or distorted affect; and (6) behavioral alterations, such as markedly increased or decreased activity, perseveration, or stereotypies.2,3 A decade later, when Leo Kanner published his seminal case series, “Autistic disturbances of affective contact,”4 the 11 youth he described were thought by many to be suffering from infantile psychosis. Presenting with social detachment, absence of communicative language, behavioral rigidity, and an interest in objects over people, these children shared many of the symptoms outlined by Potter—an apparent lack of interest in the environment, difficulties with emotional rapport, decreased affect and abnormal behaviors, including perseverations and stereotypies. However, Kanner’s cohort differed in one notable way—all had symptom onset within the first 2 years of life.5 This difference in illness onset and course ultimately proved to be the key factor supporting the differentiation of ASD from childhood SCZ, a conceptual shift that occurred gradually over a period of several decades. The demarcation was clarified in the 1980 publication of the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM III), which noted that the lack of psychotic symptoms and prominence of social deficits clearly distinguished ASD from SCZ.6 Thus, ASD moved out from under the umbrella of psychotic disorders and began to be considered as a separate entity. Although DSM-5 maintains nosologic separation of ASD and SCZ, comparison of the diagnostic criteria for the 2 disorders shows that they have marked similarities in clinical presentation. ASD is defined by 2 major criteria: (1) persistent deficits in social communication, social interactions, social-emotional reciprocity, and communicative behaviors and (2) restricted, repetitive patterns of behavior, interests or activities, which include stereotyped or repetitive movements, behavioral rigidity, odd or intense interests, and abnormally high or low reactivity to sensory stimuli.7 The DSM-5 diagnostic criteria for SCZ require at least 2 of the following symptoms be present: hallucinations, delusions, disorganized speech, grossly disorganized or catatonic behavior, and/or negative symptoms.7 Although hallucinations, delusions, and thought (speech) disorder are essential features of SCZ (and are not present in ASD), the negative symptoms are often more impairing, pervasive, and treatment resistant.8 These negative symptoms, which include asociality, alogia, and low levels of emotional expression (also an indicator of impaired nonverbal communication) can be construed more broadly as deficits in social communication and motivation. Thus, the negative symptoms of SCZ share many features in common with the social deficits of ASD. Similarly, grossly disorganized or abnormal motor behavior as described in SCZ includes a number of signs and symptoms consistent with those of ASD Criterion B, such as repeated stereotyped movements, echolalia, unpredictable agitation, and decreased interaction with or interest in one’s environment. Given the shared clinical manifestations of SCZ and ASD, it is not surprising that the 2 disorders co-occur frequently. Nearly 30% of youth diagnosed with childhood onset SCZ in a large NIH cohort had co-morbid ASD,9 and both epidemiologic and retrospective clinical studies suggest an association between ASD diagnosis or childhood autistic traits and later psychotic experiences.10,11 Similar patterns of cognitive deficits have also been noted. For example, studies designed to assess systems for social processes demonstrate that facial recognition and emotion processing are impaired in SCZ12 as well as in ASD.13 Further, both groups have been shown to have deficits in social cueing associated with eye gaze, as well as in performance on theory of mind tasks.14–17 Meta-analyses of SCZ reports suggests that deficits are correlated with negative symptoms and disorganization.18,19 Autism and SCZ also appear to share biological underpinnings that may begin very early in neural development. Whole exome sequencing analyses implicate ASD and SCZ risk genes in the development of deep layer cortical projection neurons in the prefrontal and primary motor-somatosensory cortical (ASD) and dorsolateral and ventrolateral prefrontal cortical (SCZ) regions, respectively.20 A number of neurodevelopmental disorders with known genetic defects are associated with high rates of both ASD and SCZ, including 22q11.2 Deletion Syndrome, Shank3 mutations, and duplications at the Williams Syndrome locus (7q11.23), among others.20–22 Epigenetic effects and alterations in copy number variants have been reported to contribute to abnormalities of cerebral cytoarchitecture that have been related to SCZ and ASD.11 In addition, environmental factors, such as advanced paternal age and maternal infection/immune activation during pregnancy, have been reported to increase risk of both ASD and SCZ.23,24 In 1955, Eisenberg and Kanner wrote that early infantile autism was a “total psychobiological disorder,” and suggested that it was “probably related generically” to SCZ.5 After more than 5 decades of research and clinical experience, we are beginning to appreciate the veracity of their prediction, and to understand the nature of this relationship. Exploring commonalities between SCZ and ASD, while appreciating salient differences between the 2 disorders, should provide new insights into their etiology, pathophysiology, treatment, and prevention. To forward these efforts, the Schizophrenia Bulletin will provide occasional special features giving emphasis to key similarities and differences between SCZ and ASD and also welcomes high quality reports addressing these issues.

A PROSPECTIVE STUDY OF SEVERE IRRITABILITY IN YOUTHS: 2- AND 4-YEAR FOLLOW-UP

Severe, chronic irritability is receiving increased research attention, and is the cardinal symptom of a new diagnostic category, disruptive mood dysregulation disorder (DMDD). Although data from epidemiological community samples suggest that childhood chronic irritability predicts unipolar depression and anxiety in adulthood, whether these symptoms are stable and cause ongoing clinical impairment is unknown. The present study presents 4‐year prospective and longitudinal diagnostic and impairment data on a clinical sample of children selected for symptoms of severe irritability (operationalized as severe mood dysregulation [SMD]).

Reward feedback processing in children and adolescents: medial frontal theta oscillations.

We examined event-related electroencephalography (EEG) oscillations, including event-related spectral perturbations (ERSP) and intertrial coherence (ITC), to compare feedback processing during a chance-based reward vs. non-reward task in groups of 10-12-year-old (n=42), 13-14-year-old (n=34) and 15-17-year-olds (n=32). Because few, if any studies have applied these analytic methods to examine feedback processing in children or adolescents, we used a fine-grained approach that explored one half hertz by 16ms increments during feedback (no win vs. win events) in the theta (4-8Hz) frequency band. Complex wavelet frequency decomposition revealed that no win feedback was associated with enhanced theta power and phase coherence. We observed condition and age-based differences for both ERSP and ITC, with stronger effects for ITC. The transition from childhood to early adolescence (13-14yrs.) was a point of increased differentiation of ITC favoring no win vs. wins feedback and also compared to children or older adolescents, a point of heightened ITC for no win feedback (quadratic effect).

The variable heart: High frequency and very low frequency correlates of depressive symptoms in children and adolescents.

BACKGROUND Work examining the link between lower heart rate variability (HRV) and depression in children and adolescents is lacking, especially in light of the physiological changes that occur during pubertal development. METHOD We investigated the association between spectral measures of resting HRV and depressive symptoms among 127 children and adolescents, ages 10-17. Using spectral analysis, we evaluated (1) the association between relative high frequency (HF) HRV and depressive symptoms; (2) the predictive power of relative HF HRV for depressive symptoms in the context of relative low frequency (LF) and relative very low frequency (VLF) HRV; and (3) the relationship between relative HF, LF, and VLF band activity, age and pubertal maturation. RESULTS Consistent with previous work, results revealed that relative HF HRV was negatively associated with self-reported depressive symptoms. As well, relative VLF HRV was positively associated with depressive symptoms. Regression analyses revealed that relative HF HRV and relative VLF HRV significantly predicted self-report depressive symptoms while controlling for age, sex and pubertal maturation, with relative VLF HRV emerging as the strongest indicator of depressive symptoms. Developmental findings also emerged. Age and pubertal maturation were negatively associated with relative HF HRV and positively correlated with relative VLF HRV. CONCLUSIONS Results provide support for the relationship between HRV and depression and suggest that both HF and VLF HRV are relevant to depression symptom severity. Findings also reinforce the importance of considering pubertal development when investigating HRV-depression associations in children and adolescents. LIMITATIONS Influences on cardiac control including physical activity levels and exercise patterns could be controlled in future work. Our data speak to a depressive symptom dimension and relative spectral power HRV. Thus, we cannot make strong claims about relative spectral power HRV and clinical depression.

High frequency heart-rate variability predicts adolescent depressive symptoms, particularly anhedonia, across one year

BACKGROUND Few prospective studies examine the link between lower heart rate variability (HRV) and depression symptoms in adolescents. A recent animal model specifically links HRV to anhedonia, suggesting a potential translational model for human research. METHOD We investigated the association between spectral measures of resting HRV and depressive symptoms measured one year later, among 73 adolescents, aged 11-18 years. We evaluated (1) the predictive power of relative high frequency (HF) HRV, relative low frequency (LF) and relative very low frequency (VLF) HRV for depressive symptoms; and (2) the relative strength of association between HF HRV and depressive symptomatology (anhedonia, negative mood, interpersonal problems, ineffectiveness, negative self-esteem). RESULTS HF HRV significantly predicted self-reported depressive symptoms across one year, controlling for age, puberty and sex. HF HRV was most strongly associated with anhedonia one year later, after considering other facets of depressive symptomatology. CONCLUSIONS Results provide support for the prospective relationship between relative HF HRV and depressive symptoms among adolescents across one year. Findings concur with rodent models that suggest a specific link between HF HRV and anhedonia. LIMITATIONS We investigated relative spectral power HF HRV and depressive symptom dimensions. We cannot make strong claims about these associations in clinical depression. Physical activity levels could be controlled in future work.

Classic bladder exstrophy in a nonhuman primate: a comparative analysis

OBJECTIVES To describe the pelvic floor musculature and bony pelvic anatomy in a case of naturally occurring classic bladder exstrophy in a rhesus monkey, the first reported case in the animal population since 1832, and compare the results to exstrophy seen in human newborns. METHODS A 7-day-old male rhesus monkey with classic bladder exstrophy was examined by a pediatric urologist and primate veterinarian before being killed. A multidetector row computed tomography study with three-dimensional reconstruction was obtained, and a comparison computed tomography study of a 17-day-old male human with exstrophy was also reconstructed three dimensionally. The bony pelvis and pelvic floor muscular anatomy of both subjects were then examined and compared. RESULTS On gross examination, a similar appearance of classic bladder exstrophy in the rhesus monkey and human newborn were noted, including an open exposed bladder, associated penile epispadias, and widely separated pubic bones. The evaluation of the three-dimensional models showed a similar orientation of the bony pelvis in both the rhesus and the human newborn. The iliac wings were significantly rotated outward, and the sacroiliac joint was 10 degrees wider than that seen in normal children. The exstrophy pelvic floor in both the rhesus and the newborn was markedly flattened, with approximately 33% of the muscle located anterior to the rectum to support the pelvic structures (normal children have 50% of their levator ani anterior to the rectum). CONCLUSIONS By using advancements in imaging modalities, this study illustrated that naturally occurring classic bladder exstrophy in the human newborn and rhesus monkey were identical in both external appearance and internal anatomy.