Radek Ptacek

Comparing Bioinformatic Gene Expression Profiling Methods: Microarray and RNA-Seq

Understanding the control of gene expression is critical for our understanding of the relationship between genotype and phenotype. The need for reliable assessment of transcript abundance in biological samples has driven scientists to develop novel technologies such as DNA microarray and RNA-Seq to meet this demand. This review focuses on comparing the two most useful methods for whole transcriptome gene expression profiling. Microarrays are reliable and more cost effective than RNA-Seq for gene expression profiling in model organisms. RNA-Seq will eventually be used more routinely than microarray, but right now the techniques can be complementary to each other. Microarrays will not become obsolete but might be relegated to only a few uses. RNA-Seq clearly has a bright future in bioinformatic data collection.

Sleep disorders and daytime sleepiness in children with attention-deficit/hyperactivity disorder: A two-night polysomnographic study with a multiple sleep latency test

OBJECTIVE To evaluate sleep macrostructure, sleep disorders incidence and daytime sleepiness in attention-deficit/hyperactivity disorder (ADHD) affected children compared with controls. METHODS Thirty-one patients (26 boys, 5 girls, mean age 9.3±1.7, age range 6-12 years) with ADHD diagnosed according to DSM-IV criteria, without comorbid psychiatric or other disorders, as never before pharmacologically treated for ADHD. The controls were 26 age- and sex-matched children (22 boys, 4 girls, age range 6-12 years, mean age 9.2±1.5). Nocturnal polysomnography (PSG) was performed for two nights followed by the multiple sleep latency test (MSLT). RESULTS No differences between the two groups comparing both nights were found in the basic sleep macrostructure parameters or in the time (duration) of sleep onset. A first-night effect on sleep variables was apparent in the ADHD group. Occurrence of sleep disorders (sleep-disordered breathing [SDB], periodic limb movements in sleep [PLMS], parasomnias) did not show any significant differences between the investigated groups. A statistically significant difference (p=0.015) was found in the trend of the periodic limb movement index (PLMI) between two nights (a decrease of PLMI in the ADHD group and an increase of PLMI in the control group during the second night). While the mean sleep latency in the MSLT was comparable in both groups, children with ADHD showed significant (sleep latency) inter-test differences (between tests 1 and 2, 1 and 4, 1 and 5, p<0.01). CONCLUSION After the inclusion of adaptation night and exclusion of psychiatric comorbidities, PSG showed no changes in basic sleep parameters or sleep timing, or in the frequency of sleep disorders (SDB, PLMS) in children with ADHD compared with controls, thus not supporting the hypothesis that specific changes in the sleep macrostructure and sleep disturbances are connected with ADHD. A first-night effect on sleep variables was apparent only in the ADHD group. Though we found no proof of increased daytime sleepiness in children with ADHD against the controls, we did find significant vigilance variability during MSLT in the ADHD group, possibly a sign of dysregulated arousal.

Salivary Melatonin Rhythm as a Marker of the Circadian System in Healthy Children and Those With Attention-Deficit/Hyperactivity Disorder

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood. Problems with sleep structure, efficiency, and timing have been reported in some, but not all, studies on ADHD children. As the sleep-wake cycle belongs to circadian rhythms, the timekeeping circadian system might be involved in ADHD. To assess whether the circadian system of ADHD children differs from that of controls, the rhythm of the pineal hormone melatonin was used as a reliable marker of the system. Saliva from 34 ADHD and 43 control 6- to 12-yr-old children was sampled at 2-h intervals throughout the entire 24-h cycle, and the melatonin profiles of the ADHD and control children were compared. The nocturnal melatonin peaks of the ADHD and control group did not differ significantly. The high nocturnal interindividual variability of the peaks seen in adulthood was present already in the studied children. The 24-h melatonin profiles of all the ADHD subjects did not differ significantly from those of the control subjects. Categorization of subjects according to age, into groups of 6- to 7-yr-old (9 ADHD, 5 control), 8- to 9-yr-old (16 ADHD, 26 control), and 10- to 12-yr-old (9 ADHD, 12 control) children, revealed significant differences between the ADHD and control group in the melatonin rhythm waveform, but not in nocturnal melatonin peaks; the peaks were about the same in both groups and did not change significantly with increasing age. In the oldest, but not in the younger, children, the melatonin signal duration in the ADHD group was shorter than in the control group. The difference might be due to the fact that whereas in the control group both the evening melatonin onset and the morning offset phase delayed in the oldest children relative to those in the youngest children, in the ADHD group only the onset, but not the offset, phase delayed with increasing age. The data may indicate subtle differences between the circadian system of ADHD and control children during development. (Author correspondence: sumova@biomed.cas.cz)

Dopamine D4 receptor gene DRD4 and its association with psychiatric disorders

Summary Dopamine receptors control neural signals that modulates behavior. Dopamine plays an important role in normal attention; that is the reason for studying the genes of the dopaminergic system, mainly in connection with disorders of attention. DRD4 influences the postsynaptic action of dopamine and is implicated in many neurological processes, exhibits polymorphism and is one of the most studied genes in connection with psychiatric disorders. Associations were found with ADHD (attention deficit hyperactivity disorder), substance dependences, several specific personality traits, and reaction to stress. These findings have implications for pharmacogenetics. This article reviews the principle published associations of DRD4 variants with psychiatric disorders.

Disruptive patterns of eating behaviors and associated lifestyles in males with ADHD

Background Attention deficit hyperactivity disorder (ADHD) is a neurological/behavioral disorder characterized by inattention or hyperactivity and impulsivity, or combined symptomatology. Children with ADHD are predisposed to irregular and/or impulsive eating patterns often leading to compromised physical condition. The goal of the present study was to statistically evaluate parental scoring of patterned eating behaviors and associated lifestyles within a cohort of 100 boys diagnosed with ADHD in comparison to age-matched male controls. Material/Methods The study population consisted of 100 boys aged 6–10 years diagnosed with mixed type ADHD by DSM-IV criteria and 100 aged-matched healthy male control subjects. Patterns of eating behaviors and associated lifestyles were scored by structured parental interviews using a nominal rating scale. Results Interview scores indicated statistically significant differences in patterned eating behaviors in subjects with ADHD in comparison to healthy controls. Notably, subjects diagnosed with ADHD exhibited markedly diminished adherence to a traditional breakfast, lunch, and dinner schedule, which was linked to a significantly higher frequency (>5/day) of irregular eating times. In the ADHD cohort, disruptive patterns of eating behaviors were associated with diminished nutritional value of ingested food (expressed as lowered content of fruits and vegetables) and increased consumption of sweetened beverages. Conclusions Disruptive patterns of eating behaviors, metabolically unfavorable nutritional status, and diminished physical activities of male children diagnosed with ADHD are linked to compromised growth and development and appearance of metabolic diseases in adulthood.

Attention deficit hyperactivity disorder and disordered eating behaviors: links, risks, and challenges faced

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that often persists in adulthood. It is defined by inattention and/or hyperactivity–impulsivity. ADHD is associated with many comorbidities, including eating disorders (EDs). In the last decade, studies have reported that ADHD is linked with binge EDs, bulimia nervosa, and anorexia nervosa. Many postulates have been proposed to explain the association: 1) impulsive behavior in ADHD patients leads to disordered eating behavior; 2) other psychologic comorbidities present in ADHD patients account for eating behavior; 3) poor eating habits and resulting nutritional deficiencies contribute to ADHD symptoms; and 4) other risk factors common to both ADHD and EDs contribute to the coincidence of both diseases. Additionally, sex differences become a significant issue in the discussion of EDs and ADHD because of the higher incidence of bulimia nervosa and anorexia nervosa in females and the ability of females to mask the symptoms of ADHD. Interestingly, both EDs and ADHD rely on a common neural substrate, namely, dopaminergic signaling. Dopaminergic signaling is critical for motor activity and emotion, the latter enabling the former into a combined motivated movement like eating. This linkage aids in explaining the many comorbidities associated with ADHD. The interconnection of ADHD and EDs is discussed from both a historical perspective and the one based on the revealing nature of its comorbidities.

Convergent dysregulation of frontal cortical cognitive and reward systems in eating disorders

A substantive literature has drawn a compelling case for the functional involvement of mesolimbic/prefrontal cortical neural reward systems in normative control of eating and in the etiology and persistence of severe eating disorders that affect diverse human populations. Presently, we provide a short review that develops an equally compelling case for the importance of dysregulated frontal cortical cognitive neural networks acting in concert with regional reward systems in the regulation of complex eating behaviors and in the presentation of complex pathophysiological symptoms associated with major eating disorders. Our goal is to highlight working models of major eating disorders that incorporate complementary approaches to elucidate functionally interactive neural circuits defined by their regulatory neurochemical phenotypes. Importantly, we also review evidence-based linkages between widely studied psychiatric and neurodegenerative syndromes (e.g., autism spectrum disorders and Parkinson’s disease) and co-morbid eating disorders to elucidate basic mechanisms involving dopaminergic transmission and its regulation by endogenously expressed morphine in these same cortical regions.

Parkinson’s disease, L-DOPA, and endogenous morphine: A revisit

Summary Clinical observations stemming from widespread employment of restorative L-3,4-dihydroxyphenylalanine (L-DOPA) therapy for management of dyskinesia in Parkinson’s Disease (PD) patients implicate a regulatory role for endogenous morphine in central nervous system dopamine neurotransmission. Reciprocally, it appears that restorative L-DOPA administration has provided us with a compelling in vivo pharmacological model for targeting peripheral sites involved in endogenous morphine expression in human subjects. The biological activities underlying endogenous morphine expression and its interaction with its major precursor dopamine strongly suggest that endogenous morphine systems are reciprocally dysregulated in PD. These critical issues are examined from historical and current perspectives within our short review.

Mitochondria, Microbiome and Their Potential Psychiatric Modulation

Pervasive developmental disorders, or autism spectrum disorders, are multifaceted and have a high rate of occurrence. Additionally, the origin of Autism appears to be multidimensional and largely unknown. Thus, it would appear novel approaches and concepts are needed in this area of scientific endeavor. In this regard, microbial cells harbored within the human gut and elsewhere are being studied to understand their multi-functional properties and their ability to affect physiological activities in their “host” organism. The communities of approximately 10 trillion microbial cells that live within the gut are involved in functions such as metabolism, nutrition and immune regulation. We and others surmise this microbiota can contribute to disruption of normal activities, causing harmful pathologies such as gastrointestinal complications, obesity, and diabetes and autism. They have the ability to trigger inappropriate immune activation, especially macrophages, which can travel from the gut and penetrate the blood brain barrier and communicate inappropriately with neural cells, altering behavior. Normally these immune cells can enter the brain and become microglia. However, being abnormally stimulated, many more can enter the brain, awakening the sentinel microglia and establishing a proinflammatory state, inducing hypoxia (altering mitochondrial performance). Thus, the microbiome has the potential to extend its influence into the brain, suggesting this may also take place within the parameters of normal activity. In part, the behavioral outcome of such an inappropriate invasion would depend on the region(s) penetrated, manifesting itself with a multidimensional behavioral profile such as occurs in autism.

Low dose morphine adjuvant therapy for enhanced efficacy of antipsychotic drug action: Potential involvement of endogenous morphine in the pathophysiology of schizophrenia

Summary Major thematic threads linking extensive preclinical and clinical efforts have established a working mechanistic scheme whereby atypical antipsychotic drugs ameliorate negative DSM IV diagnostic criteria by effecting relatively potent blockade of serotonin (5-HT)(2A) receptors coupled with weaker antagonism of dopamine D(2) receptors in frontal cortical areas. These contentions are more or less supported by in vitro binding experiments employing cloned receptors on cultured cells, although significant functional involvement of 5-HT(2C) receptors has also been proposed. It is interesting that a key statistical analysis indicates a major shift in usage back to typical antipsychotic agents for management of schizophrenia from 1995–2008, whereas off-label usage of atypical antipsychotic agents was markedly increased or expanded for bipolar affective disorder. Importantly, meta-analyses generally did not support efficacy differences between the other atypical antipsychotics compared with the older typical agents. A critical examination of putative functional linkages of morphine and its type-selective mu opioid receptor to higher order cortical regulation of cognitive processes may provide novel insights into human behavioral processes that are severely impaired in schizophrenia spectrum disorders.