Attention-deficit/hyperactivity disorder and the menstrual cycle: Theory and evidence.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that exhibits striking sex differences in symptoms, prevalence, and associated problems across development. Etiological factors and mechanisms underlying these sex differences remain one of the most understudied aspects of this disorder. The current paper seeks to provide a novel theoretical framework for understanding this phenomenon by reviewing evidence that females with ADHD may experience a "double whammy" of organizational and activational pubertal hormonal effects. We propose a novel theory of activational effects of cyclical circulating ovarian hormones on ADHD with increasing risk at times of rapid declines in estrogen. These declines may decrease executive function and trait control at two points of the cycle characterized by biphasic affective risk: (1) increases in approach/risk-taking behaviors at mid-cycle (periovulatory) and (2) increases in avoidance/negative affect perimenstrually. Low estrogen and control may then interact with increases in positive and negative affect, respectively, to increase hyperactivity-impulsivity symptoms post-ovulation and inattention symptoms perimenstrually. These interactions may be exacerbated by organizational pubertal effects on relatively overdeveloped limbic circuitry and adolescent-specific social pressures magnified in females with ADHD.

Enteric neural crest-derived cells promote their migration by modifying their microenvironment through tenascin-C production.

The enteric nervous system (ENS) is derived from vagal and sacral neural crest cells that migrate, proliferate, and differentiate into enteric neurons and glia within the gut wall. The mechanisms regulating enteric neural crest-derived cell (ENCC) migration are poorly characterized despite the importance of this process in gut formation and function. Characterization of genes involved in ENCC migration is essential to understand ENS development and could provide targets for treatment of human ENS disorders. We identified the extracellular matrix glycoprotein tenascin-C (TNC) as an important regulator of ENCC development. We find TNC dynamically expressed during avian gut development. It is absent from the cecal region just prior to ENCC arrival, but becomes strongly expressed around ENCCs as they enter the ceca and hindgut. In aganglionic hindguts, TNC expression is strong throughout the outer mesenchyme, but is absent from the submucosal region, supporting the presence of both ENCC-dependent and independent expression within the gut wall. Using rat-chick coelomic grafts, neural tube cultures, and gut explants, we show that ENCCs produce TNC and that this ECM protein promotes their migration. Interestingly, only vagal neural crest-derived ENCCs express TNC, whereas sacral neural crest-derived cells do not. These results demonstrate that vagal crest-derived ENCCs actively modify their microenvironment through TNC expression and thereby help to regulate their own migration.

Presence of intramucosal neuroglial cells in normal and aganglionic human colon.

The enteric nervous system (ENS) is composed of neural crest-derived neurons (also known as ganglion cells) the cell bodies of which are located in the submucosal and myenteric plexuses of the intestinal wall. Intramucosal ganglion cells are known to exist but are rare and often considered ectopic. Also derived from the neural crest are enteric glial cells that populate the ganglia and the associated nerves, as well as the lamina propria of the intestinal mucosa. In Hirschsprung disease (HSCR), ganglion cells are absent from the distal gut because of a failure of neural crest-derived progenitor cells to complete their rostrocaudal migration during embryogenesis. The fate of intramucosal glial cells in human HSCR is essentially unknown. We demonstrate a network of intramucosal cells that exhibit dendritic morphology typical of neurons and glial cells. These dendritic cells are present throughout the human gut and express Tuj1, S100, glial fibrillary acidic protein, CD56, synaptophysin, and calretinin, consistent with mixed or overlapping neuroglial differentiation. The cells are present in aganglionic colon from patients with HSCR, but with an altered immunophenotype. Coexpression of Tuj1 and HNK1 in this cell population supports a neural crest origin. These findings extend and challenge the current understanding of ENS microanatomy and suggest the existence of an intramucosal population of neural crest-derived cells, present in HSCR, with overlapping immunophenotype of neurons and glia. Intramucosal neuroglial cells have not been previously recognized, and their presence in HSCR poses new questions about ENS development and the pathobiology of HSCR that merit further investigation.

Invited commentary: broadening the evidence for adolescent sexual and reproductive health and education in the United States.

Scientific research has made major contributions to adolescent health by providing insights into factors that influence it and by defining ways to improve it. However, US adolescent sexual and reproductive health policies-particularly sexuality health education policies and programs-have not benefited from the full scope of scientific understanding. From 1998 to 2009, federal funding for sexuality education focused almost exclusively on ineffective and scientifically inaccurate abstinence-only-until-marriage (AOUM) programs. Since 2010, the largest source of federal funding for sexual health education has been the "tier 1" funding of the Office of Adolescent Health's Teen Pregnancy Prevention Initiative. To be eligible for such funds, public and private entities must choose from a list of 35 programs that have been designated as "evidence-based" interventions (EBIs), determined based on their effectiveness at preventing teen pregnancies, reducing sexually transmitted infections, or reducing rates of sexual risk behaviors (i.e., sexual activity, contraceptive use, or number of partners). Although the transition from primarily AOUM to EBI is important progress, this definition of evidence is narrow and ignores factors known to play key roles in adolescent sexual and reproductive health. Important bodies of evidence are not treated as part of the essential evidence base, including research on lesbian, gay, bisexual, transgender, queer, and questioning (LGBTQ) youth; gender; and economic inequalities and health. These bodies of evidence underscore the need for sexual health education to approach adolescent sexuality holistically, to be inclusive of all youth, and to address and mitigate the impact of structural inequities. We provide recommendations to improve US sexual health education and to strengthen the translation of science into programs and policy.

Impaired contextual fear-conditioning in MAM rodent model of schizophrenia.

The methylazoxymethanol acetate (MAM) rodent neurodevelopmental model of schizophrenia exhibits aberrant dopamine system activation attributed to hippocampal dysfunction. Context discrimination is a component of numerous behavioral and cognitive functions and relies on intact hippocampal processing. The present study explored context processing behaviors, along with dopamine system activation, during fear learning in the MAM model. Male offspring of dams treated with MAM (20mg/kg, i.p.) or saline on gestational day 17 were used for electrophysiological and behavioral experiments. Animals were tested on the immediate shock fear conditioning paradigm, with either different pre-conditioning contexts or varying amounts of context pre-exposure (0-10 sessions). Amphetamine-induced locomotor activity and dopamine neural activity was measured 1-week after fear conditioning. Saline, but not MAM animals, demonstrated enhanced fear responses following a single context pre-exposure in the conditioning context. One week following fear learning, saline rats with 2 or 7min of context pre-exposure prior to fear conditioning also demonstrated enhanced amphetamine-induced locomotor response relative to MAM animals. Dopamine neuron recordings showed fear learning-induced reductions in spontaneous dopamine neural activity in MAM rats that was further reduced by amphetamine. Apomorphine administration confirmed that reductions in dopamine neuron activity in MAM animals resulted from over excitation, or depolarization block. These data show a behavioral insensitivity to contextual stimuli in MAM rats that coincide with a less dynamic dopamine response after fear learning.

National dissemination of cognitive-behavioral therapy for chronic pain in veterans: therapist and patient-level outcomes.

OBJECTIVE: This paper assesses the effects of training in and implementation of Cognitive-Behavioral Therapy for Chronic Pain (CBT-CP) in the US Department of Veterans Affairs (VA) health care system on therapists' CBT-CP competencies and patients' pain-related outcomes. METHODS: A total of 71 therapists participated in the VA CBT-CP Training Program. Patients included 148 Veterans treated by therapist training participants. Therapists completed a 3-day workshop followed by 6 months of weekly consultation. Therapy session tapes were rated by expert training consultants using a standardized competency rating form. Patient outcomes were assessed with measures of patient-reported pain intensity, pain-related cognitions, overall distress, depression, pain interference, and quality of life. The therapeutic alliance was also assessed. RESULTS: Among the 71 therapists who participated in the training program, 60 (85%) completed all training requirements, including competency-based performance criteria. Of the 148 Veteran patients treated, 117 (79%) completed all CBT-CP protocol sessions. Intent-to-treat analyses indicated significant improvements in pain catastrophizing, interference, quality of life, and other domains, as well as on the therapeutic alliance. DISCUSSION: Training in and implementation of CBT-CP in the VA health care system were associated with significant increases in therapist competencies to deliver CBT-CP and improvements in several domains for Veteran patients. Results support the feasibility and effectiveness of broad dissemination of CBT-CP in routine, nonpain specialty settings.

National dissemination of interpersonal psychotherapy for depression in veterans: therapist and patient-level outcomes.

OBJECTIVE: To evaluate the effects of training in and delivery of interpersonal psychotherapy (IPT) for depression throughout the U.S. Department of Veterans Affairs health care system on therapists' competency and patients' clinical outcomes. METHOD: Participants included 124 therapists and 241 veteran patients. Therapists participated in a 3-day workshop followed by 6 months of weekly group consultation. Therapy session tapes were rated by expert IPT training consultants using a standardized competency rating form. Patient outcomes were assessed with the Beck Depression Inventory-II and the World Health Organization Quality of Life-BREF. Therapeutic alliance was assessed with the Working Alliance Inventory-Short Revised. RESULTS: Of the 124 therapists receiving IPT training, 115 (93%) completed all training requirements. Therapist competence in IPT increased from their 1st patient to their 2nd for both initial (d = 0.36) and intermediate (d = 0.24) treatment phases. Of the 241 veteran patients treated with IPT, 167 (69%) completed ≥ 12 sessions. Intent-to-treat analyses indicated large overall reductions in depression (d = 1.26) and significant improvements in quality of life (d = 0.57 to 0.86) and the therapeutic alliance (d = 0.50 to 0.83). CONCLUSIONS: National IPT training in the VA health care system was associated with significant increases in therapist competencies to deliver IPT, as well as large overall reductions in depression and improvements in quality of life among veterans, many of whom presented with high levels of depression. RESULTS support the feasibility and effectiveness of broad dissemination of IPT in routine clinical settings.