Ancient balancing selection on heterocyst function in a cosmopolitan cyanobacterium.

The conventional view of bacterial adaptation emphasizes the importance of rapidly evolved changes that are highly repeatable in response to similar environments and subject to loss in the absence of selection. Consequently, genetic variation is not expected to persist over long time scales for these organisms. Here, we show that a geographically widespread gene content polymorphism has surprisingly been maintained for tens of millions of years of diversification of the multicellular cyanobacterium Fischerella thermalis. The polymorphism affects gas permeability of the heterocyst-the oxygen-sensitive, nitrogen-fixing cell produced by these bacteria-and spatial variation in temperature favours alternative alleles due to thermodynamic effects on both heterocyst function and organism fitness at physiological temperature extremes. Whether or not ancient balancing selection plays a generally important role in the maintenance of microbial diversity remains to be investigated.

Magnetic Resonance Imaging-Guided, Open-Label, High-Frequency Repetitive Transcranial Magnetic Stimulation for Adolescents with Major Depressive Disorder.

OBJECTIVE: Preliminary studies suggest that repetitive transcranial magnetic stimulation (rTMS) may be an effective and tolerable intervention for adolescents with treatment-resistant depression. There is limited rationale to inform coil placement for rTMS dosing in this population. We sought to examine and compare three localization techniques for coil placement in the context of an open-label trial of high-frequency rTMS for adolescents with treatment-resistant depression. METHODS: Ten adolescents with treatment-resistant depression were enrolled in an open-label trial of high-frequency rTMS. Participants were offered 30 rTMS sessions (10 Hz, 120% motor threshold, left 3000 pulses applied to the dorsolateral prefrontal cortex) over 6-8 weeks. Coil placement for treatment was MRI guided. The scalp location for treatment was compared with the locations identified with standard 5 cm rule and Beam F3 methods. RESULTS: Seven adolescents completed 30 rTMS sessions. No safety or tolerability concerns were identified. Depression severity as assessed with the Children's Depression Rating Scale Revised improved from baseline to treatment 10, treatment 20, and treatment 30. Gains in depressive symptom improvement were maintained at 6 month follow-up visits. An MRI-guided approach for coil localization was feasible and efficient. Our results suggest that the 5 cm rule, Beam F3, and the MRI-guided localization approaches provided variable scalp targets for rTMS treatment. CONCLUSIONS: Open-label, high-frequency rTMS was feasible, tolerable, and effective for adolescents with treatment-resistant depression. Larger, blinded, sham-controlled trials are needed for definitive safety and efficacy data. Further efforts to understand optimal delivery, dosing, and biomarker development for rTMS treatments of adolescent depression are warranted.

A 20 Year Practice Review of Electroconvulsive Therapy for Adolescents.

OBJECTIVE: Clinical reviews of practice outcomes of adolescent patients who have received electroconvulsive therapy (ECT) remain relatively rare. This study reports the clinic practice and outcome of adolescents receiving ECT at a tertiary medical center. METHODS: From April 1991 through November 2013, 51 adolescents (30 female; mean [SD] age, 16.8 [1.6] years) received ECT. The electronic medical record at the time of the first ECT session was reviewed for the clinical diagnosis, ECT lead placement and general administration, seizure duration, adverse effects, concurrent medications, and clinical outcome. RESULTS: ECT was recommended for primary mood and psychotic disorders or catatonia. Patients received a mean (SD) of 9.3 (3.5) treatments, with initial bitemporal lead placement in 36 patients (71%). Thirty-nine patients (77%) were much or very much improved based on Clinical Global Impressions-Improvement scale at the end of the acute treatment. Prolonged seizure duration (>120 seconds) was relatively common (63%) but appeared to decrease in older patients. CONCLUSIONS: This report describes the largest group of adolescents receiving ECT since 1947, and supports ECT as a safe and effective modality for most treatment-recalcitrant psychiatric illness in youth.

Treatments and Services Provided to Children Diagnosed with Bipolar Disorder.

To better understand the types and quantity of mental health services and medication usage for youth diagnosed with bipolar disorder (BD) within an integrated healthcare system, medical records were reviewed from 2000 to 2011. Eighty-five youth diagnosed with BD were identified and healthcare services (medication and psychotherapy follow-up appointments, emergency room (ER) visits, admissions, phone contacts) and visit-related details (medication usage) were abstracted for 2 years after initial BD diagnosis. Despite complex medication regimens (91.7 and 81.2 % received mood stabilizers and antipsychotic agents, respectively), medication appointments were infrequent, averaging 1 visit every 2 months. Only 36 (42 %) of 85 youth were noted to receive psychotherapy services following BD diagnosis, also averaging 1 visit every 2 months. Most (58.8 %) patients needed one or more hospitalizations during the follow-up period; nearly half (48.2 %) had psychiatric ER visits. The relative lack of psychotherapy and infrequent follow-up visits suggests need for improvement to optimize healthcare delivery.

Transcranial magnetic stimulation potentiates glutamatergic neurotransmission in depressed adolescents.

Abnormalities in glutamate neurotransmission may have a role in the pathophysiology of adolescent depression. The present pilot study examined changes in cortical glutamine/glutamate ratios in depressed adolescents receiving high-frequency repetitive transcranial magnetic stimulation. Ten adolescents with treatment-refractory major depressive disorder received up to 30 sessions of 10-Hz repetitive transcranial magnetic stimulation at 120% motor threshold with 3000 pulses per session applied to the left dorsolateral prefrontal cortex. Baseline, posttreatment, and 6-month follow-up proton magnetic resonance spectroscopy scans of the anterior cingulate cortex and left dorsolateral prefrontal cortex were collected at 3T with 8-cm(3) voxels. Glutamate metabolites were quantified with 2 distinct proton magnetic resonance spectroscopy sequences in each brain region. After repetitive transcranial magnetic stimulation and at 6 months of follow-up, glutamine/glutamate ratios increased in the anterior cingulate cortex and left dorsolateral prefrontal cortex with both measurements. The increase in the glutamine/glutamate ratio reached statistical significance with the TE-optimized PRESS sequence in the anterior cingulate cortex. Glutamine/glutamate ratios increased in conjunction with depressive symptom improvement. This reached statistical significance with the TE-optimized PRESS sequence in the left dorsolateral prefrontal cortex. High-frequency repetitive transcranial magnetic stimulation applied to the left dorsolateral prefrontal cortex may modulate glutamate neurochemistry in depressed adolescents.

Divergence with gene flow in a population of thermophilic bacteria: a potential role for spatially varying selection.

A fundamental goal of evolutionary biology is to understand how ecological diversity arises and is maintained in natural populations. We have investigated the contributions of gene flow and divergent selection to the distribution of genetic variation in an ecologically differentiated population of a thermophilic cyanobacterium (Mastigocladus laminosus) found along the temperature gradient of a nitrogen-limited stream in Yellowstone National Park. For most loci sampled, gene flow appears to be sufficient to prevent substantial genetic divergence. However, one locus (rfbC) exhibited a comparatively low migration rate as well as other signatures expected for a gene experiencing spatially varying selection, including an excess of common variants, an elevated level of polymorphism and extreme genetic differentiation along the gradient. rfbC is part of an expression island involved in the production of the polysaccharide component of the protective envelope of the heterocyst, the specialized nitrogen-fixing cell of these bacteria. SNP genotyping in the vicinity of rfbC revealed a ~5-kbp region including a gene content polymorphism that is tightly associated with environmental temperature and therefore likely contains the target of selection. Two genes have been deleted both in the predominant haplotype found in the downstream region of White Creek and in strains from other Yellowstone populations of M. laminosus, which may result in the production of heterocysts with different envelope properties. This study implicates spatially varying selection in the maintenance of variation related to thermal performance at White Creek despite on-going or recent gene flow.

Neurocognitive effects of repetitive transcranial magnetic stimulation in adolescents with major depressive disorder.

OBJECTIVES: It is estimated that 30-40% of adolescents with major depressive disorder (MDD) do not receive full benefit from current antidepressant therapies. Repetitive transcranial magnetic stimulation (rTMS) is a novel therapy approved by the US Food and Drug Administration to treat adults with MDD. Research suggests rTMS is not associated with adverse neurocognitive effects in adult populations; however, there is no documentation of its neurocognitive effects in adolescents. This is a secondary post hoc analysis of neurocognitive outcome in adolescents who were treated with open-label rTMS in two separate studies. METHODS: Eighteen patients (mean age, 16.2 ± 1.1 years; 11 females, 7 males) with MDD who failed to adequately respond to at least one antidepressant agent were enrolled in the study. Fourteen patients completed all 30 rTMS treatments (5 days/week, 120% of motor threshold, 10 Hz, 3,000 stimulations per session) applied to the left dorsolateral prefrontal cortex. Depression was rated using the Children's Depression Rating Scale-Revised. Neurocognitive evaluation was performed at baseline and after completion of 30 rTMS treatments with the Children's Auditory Verbal Learning Test (CAVLT) and Delis-Kaplan Executive Function System Trail Making Test. RESULTS: Over the course of 30 rTMS treatments, adolescents showed a substantial decrease in depression severity. Commensurate with improvement in depressive symptoms was a statistically significant improvement in memory and delayed verbal recall. Other learning and memory indices and executive function remained intact. Neither participants nor their family members reported clinically meaningful changes in neurocognitive function. CONCLUSION: These preliminary findings suggest rTMS does not adversely impact neurocognitive functioning in adolescents and may provide subtle enhancement of verbal memory as measured by the CAVLT. Further controlled investigations with larger sample sizes and rigorous trial designs are warranted to confirm and extend these findings.

Proton magnetic resonance spectroscopy as a probe into the pathophysiology of autism spectrum disorders (ASD): a review.

Proton magnetic resonance spectroscopy ((1) H-MRS) is a safe, noninvasive way of quantifying in vivo biochemical and metabolite concentration levels in individuals with Autism Spectrum Disorders (ASD). Findings to date suggest ASD is associated with widespread reduction in N-acetylaspartate (NAA), creatine plus phosphocreatine (Cr), choline-containing compounds (Cho), myo-inositol (mI), and glutamate plus glutamine plus gamma-Aminobutyric Acid (Glx); however, variable findings, and even substantial increases, are not uncommon depending on the study and/or region-of-interest. Widespread reduction of NAA, Cr, Cho, mI, and Glx in ASD likely reflects impaired neuronal function and/or metabolism related to abnormal neurodevelopmental processes. Future studies should attempt to relate (1) H-MRS findings to histological findings and control for variability in subject age and functioning level; this would assist in evaluating the relationship between (1) H-MRS metabolic levels and neuronal and glial cell densities, as well as neurodevelopmental process associated with ASD. Furthermore, more longitudinal (1) H-MRS studies are needed in both control and ASD subjects to attempt to standardize metabolite levels across different developmental periods in well-defined endophenotypes. This will provide for a standard rubric for which metabolic aberrations (as well as treatment responses) can be measured. With higher magnetic field strengths and spectral-editing techniques capable of quantifying less-concentrated metabolites, (1) H-MRS will continue to be an important tool in ASD research.

Methohexital-induced seizures during electroconvulsive therapy.

Methohexital is a common anesthetic agent used for electroconvulsive therapy. In the adult literature, there are a few case reports of tonic-clonic seizures occurring immediately after the administration of methohexital. However, to date, there are no reports of this occurrence in children or adolescents. This case documents a generalized tonic-clonic seizure in a 15-year-old girl after receiving 60 mg of methohexital and numerous prior episodes of bitemporal electroconvulsive therapy.

Psychiatric pharmacogenomics in pediatric psychopharmacology.

This article provides an overview of where psychiatric pharmacogenomic testing stands as an emerging clinical tool in modern psychotropic prescribing practice, specifically in the pediatric population. This practical discussion is organized around the state of psychiatric pharmacogenomics research when choosing psychopharmacologic interventions in the most commonly encountered mental illnesses in youth. As with the rest of the topics on psychopharmacology for children and adolescents in this publication, a clinical vignette is presented, this one highlighting a clinical case of a 16 year old genotyped during hospitalization for recalcitrant depression.

Increased cortical excitability with prefrontal high-frequency repetitive transcranial magnetic stimulation in adolescents with treatment-resistant major depressive disorder.

OBJECTIVE: To examine changes in motor cortical excitability in adolescent subjects receiving 30 sessions of high-frequency prefrontal repetitive transcranial magnetic stimulation (rTMS). METHODS: Eight adolescents with treatment-resistant major depressive disorder (MDD) enrolled in an open augmentation trial of 10 Hz rTMS. Resting motor thresholds were obtained by the visualization of movement method with a maximum likelihood threshold hunting computer algorithm at baseline and after every five sessions of rTMS. Motor threshold was recorded as the percentage of total machine output at each measurement. RESULTS: Motor threshold data from baseline, weeks 2, 4, and 5 were included in a mixed model repeated measure analysis to examine a change in least square mean effect over time. The omnibus effect did not reach statistical significance (F=1.25, p=0.32). However, multiple comparisons from the overall model demonstrated a decrease in the least square mean motor threshold. The mean contrast from baseline to week 5 approached significance (p=0.07). Moreover, a post-hoc analysis with a Wilcoxon signed ranks test demonstrated a significant decrease at week 5 (p=0.03). CONCLUSIONS: This suggests that high-frequency rTMS may increase cortical excitability in adolescents with treatment-resistant MDD.

Applications of transcranial magnetic stimulation (TMS) in child and adolescent psychiatry.

Transcranial magnetic stimulation (TMS) is emerging as a new treatment and neurophysiological research tool for psychiatric disorders. Recent publications suggest that this modality will also serve as a treatment and research tool in child and adolescent psychiatry. Current reports on therapeutic trials of repetitive transcranial magnetic stimulation (rTMS) in adolescents have primarily focused on depression. However, other pilot work involves the treatment of attention-deficit/hyperactivity disorder (ADHD), autism and schizophrenia. Neurophysiological studies typically utilize single and paired-pulse TMS paradigms which index cortical excitability and inhibition. Initial studies have focused on ADHD, autism, and depression. General knowledge regarding TMS among child and adolescent psychiatrists is lacking. The aim of this review is to provide an overview of TMS in the context of child and adolescent psychiatry, discuss recent therapeutic and neurophysiological studies, and examine relevant ethical considerations.

Psychiatric comorbidity in children and adolescents with restless legs syndrome: a retrospective study.

OBJECTIVE: Children and adolescents with restless legs syndrome (RLS) are commonly diagnosed with comorbid attention deficit hyperactivity disorder and behavioral disturbances. Uncertainty exists over the significance of other co-occurring psychiatric disorders and their pharmacologic management in children with RLS. The purpose of this study was to determine the prevalence and nature of psychiatric disorders in children with RLS and to describe the use of psychotropic medications in our study cohort. METHODS: The electronic medical records of children younger than 18 years of age who had been diagnosed with RLS between January 1, 2003, and December 31, 2009, were reviewed. Only those patients whose findings were consistent with the 2003 NIH workshop diagnostic criteria for probable or definite restless legs syndrome were included in this study. The medical records were cross-referenced for encounters with a child psychiatrist or psychologist. Likewise, only psychiatric diagnoses whose medical records explicitly reflected DSM-IV diagnostic criteria for psychiatric disorder(s) were included. Demographic data, serum ferritin, psychotropic medications, and in some cases, the results of pharmacogenomic testing were included in the data analysis in an ad hoc fashion. RESULTS: We found 374/922 patients who met diagnostic criteria for childhood onset RLS. The mean age of the subjects was 10.6 years (range 0 to 18) and the male to female ratio was approximately 1:1. Overall, 239/374 (64%) patients with RLS had one or more comorbid psychiatric disorders. Attention deficit hyperactivity disorder was found in 94/374 (25%) patients, mood disturbances were found in 109/374 (29.1%) patients, anxiety disorders in 43/374 (11.5%) patients, and behavioral disturbances in 40/374 (10.9%) patients. Attention deficit hyperactivity disorder and disruptive behavior disorders were more common in males (OR = 1.94 for both), whereas mood disturbances and anxiety disorders were more common in females (OR = 1.6 and 1.26, respectively). Mean serum ferritin levels derived from all patients without any psychiatric disorder were compared to all patients with one or more psychiatric disorder. No differences were found. The number of new psychotropic medication trials increased significantly with increase in patient age. Stimulants and antidepressant medications were the most commonly prescribed agents. As a part of clinical care, 15 of these patients underwent pharmacogenomic testing. Metabolic abnormalities were predicted by genotyping in 12/15 (80%) patients. CONCLUSION: Comorbid psychiatric conditions occurred in two-thirds of children with RLS, underscoring the need for multidisciplinary management of this condition. An important relationship might exist between psychotropic medication, and possibly pharmacogenomic factors, in children and adolescents with symptoms of restless legs syndrome. These findings are consistent and build on those reported in the adult literature.

Adjunctive use of repetitive transcranial magnetic stimulation in depressed adolescents: a prospective, open pilot study.

OBJECTIVE: Depression is often a serious and debilitating illness in adolescents. Unfortunately, a significant number of adolescents do not respond to antidepressant medications or psychotherapy. Repetitive transcranial magnetic stimulation (rTMS) is a novel treatment intervention shown to benefit depression in adults. This study considered rTMS as an adjunctive treatment in adolescents with major depressive disorder. METHOD: This prospective, open, multicenter trial of active adjunctive rTMS was conducted with 8 adolescents with DSM-IV-TR major depressive disorder (MDD) that had not responded sufficiently to 2 adequate antidepressant medication trials. All subjects were maintained on a stable dose of a selective serotonin reuptake inhibitor during the trial. Thirty daily rTMS treatments were given 5 days per week over 6 to 8 weeks. rTMS was applied to the left dorsolateral prefrontal cortex (120% of motor threshold; 10 Hz; 4-second trains; 26-second intertrain interval; 75 trains) for a total of 3,000 stimulations per treatment session. RESULTS: Seven of 8 adolescents completed all 30 treatments. rTMS was well tolerated, and no significant safety issues were identified. Suicidal ideation was present at baseline in 3 of the adolescents, and it improved during treatment. The primary outcome measure was the Children's Depression Rating Scale-Revised (CDRS-R); results improved significantly from baseline (mean [SD]) (65.9 [6.6]) to treatment 10 (50.9 [12]), P < .02. The CDRS-R scores continued to improve through the rTMS treatment series at treatment 20 (40.1 [14]), P < .01; treatment 30 (32.6 [7.3]), P < .0001; and at 6-month follow-up (32.7 [3.8]), P < .0001. CONCLUSIONS: This prospective open trial suggests that rTMS is a safe, feasible, and potentially effective adjunctive therapy for treatment-resistant MDD in adolescents. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00587639.

Pain during transcranial magnetic stimulation in youth.

Pain or discomfort at the site of stimulation is a common side effect of transcranial magnetic stimulation. Relevant physiology and predisposing factors have not been adequately described. Literature regarding work with minors is even more limited. The authors present two cases from a child and adolescent neurophysiology transcranial magnetic stimulation protocol and one case from a therapeutic study of repetitive transcranial magnetic stimulation in adolescents with treatment-resistant major depressive disorder. Relevant literature is reviewed. Potential subjects, parents, and study teams should be well aware of this potential side effect in child and adolescent populations. Subjects with anxiety disorders may be prone to pain during these procedures. Further work could assist in identifying predisposed individuals, refining the informed consent process, and implementing procedures to minimize discomfort.

The emerging role for repetitive transcranial magnetic stimulation in optimizing the treatment of adolescent depression.

Major depressive disorder (MDD) in adolescents is a common illness and significant public health problem. Treatment is challenging because of recurrences and limited modalities. Selective serotonin reuptake inhibitors and cognitive behavioral therapy are considered the standard of care in severe or treatment-resistant MDD in this age group. However, responses to these interventions are often suboptimal. A growing body of research supports the efficacy of repetitive transcranial magnetic stimulation (rTMS) for the treatment of MDD in adults. Induced seizures are a primary safety concern, although this is rare with appropriate precautions. There is, however, limited experience with rTMS as a therapeutic intervention for adolescent psychiatric disturbances. This review will summarize the rTMS efficacy and safety data in adults and describe all published experience with adolescent MDD. Applications in other adolescent psychiatric illnesses such as schizophrenia and attention-deficit/hyperactivity disorder are reviewed. Safety and ethical issues are paramount with investigational treatments in adolescent psychiatric illnesses. However, further research with rTMS in adolescent MDD is imperative to establish standards for optimal stimulation site, treatment parameters, and its role in treatment algorithms. These may diverge from adult data. Early intervention with neuromodulation could also hold the promise of addressing the developmental course of dysfunctional neurocircuitry.

Psychiatric manifestations of Creutzfeldt-Jakob disease: a 25-year analysis.

This study characterizes the type and timing of psychiatric manifestations in sporadic Creutzfeldt-Jakob disease (sCJD). Historically, sCJD has been characterized by prominent neurological symptoms, while the variant form (vCJD) is described as primarily psychiatric in presentation and course: A retrospective review of 126 sCJD patients evaluated at the Mayo Clinic from 1976-2001 was conducted. Cases were reviewed for symptoms of depression, anxiety, psychosis, behavior dyscontrol, sleep disturbances, and neurological signs during the disease course. Eighty percent of the cases demonstrated psychiatric symptoms within the first 100 days of illness, with 26% occurring at presentation. The most commonly reported symptoms in this population included sleep disturbances, psychotic symptoms, and depression. Psychiatric manifestations are an early and prominent feature of sporadic CJD, often occurring prior to formal diagnosis.