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Biomedical subjects

Martin H Teicher

Publications and source records attributed to Martin H Teicher.

At least 19 recordsLinked to original sources
PubMed2006

A polymorphism in the norepinephrine transporter gene alters promoter activity and is associated with attention-deficit hyperactivity disorder.

The norepinephrine transporter critically regulates both neurotransmission and homeostasis of norepinephrine in the nervous system. In this study, we report a previously uncharacterized and common A/T polymorphism at -3081 upstream of the transcription initiation site of the human norepinephrine transporter gene [solute carrier family 6, member 2 (SLC6A2)]. Using both homologous and heterologous promoter-reporter constructs, we found that the -3081(T) allele significantly decreases promoter function compared with the A allele. Interestingly, this T allele creates a new palindromic E2-box motif that interacts with Slug and Scratch, neural-expressed transcriptional repressors binding to the E2-box motif. We also found that both Slug and Scratch repress the SLC6A2 promoter activity only when it contains the T allele. Finally, we observed a significant association between the -3081(A/T) polymorphism and attention-deficit hyperactivity disorder (ADHD), suggesting that anomalous transcription factor-based repression of SLC6A2 may increase risk for the development of attention-deficit hyperactivity disorder and other neuropsychiatric diseases.

Alleles↗
PubMed2006

Methylphenidate blood levels and therapeutic response in children with attention-deficit hyperactivity disorder: I. Effects of different dosing regimens.

BACKGROUND AND PURPOSE: Methylphenidate (MPH) is a drug of choice for treating attention-deficit/hyperactivity disorder (ADHD), although its use has been complicated by its short duration of action. The development of ideal long-acting preparations requires detailed understanding of the pharmacokinetic and pharmacodynamic consequences of complex dosing regimens. The purpose of this study was to ascertain if administration paradigms that produce stable or rising MPH levels alter the rate with which MPH is absorbed, and to determine how effectively long-acting administration paradigms compare with thrice daily administration of immediate-release MPH. METHOD: Forty-eight boys diagnosed with ADHD (mean age 10.6 +/- 1.1 year) participated in this double-blind, parallel group study to evaluate the pharmacokinetics and efficacy and of 1 mg/kg/day MPH administered in five different paradigms and placebo. Objective measures of activity and attention (McLean Motion Attention Test; M-MAT) and plasma measures of d- and l-MPH were obtained hourly during the course of a 12-hour laboratory session. RESULTS: The rate of absorption and elimination of d-MPH was dependent on the pattern of administration, particularly on the initial bolus concentration. This suggests that d-MPH may act on the gastrointestinal system to slow absorption of additional d-MPH. There were significant differences among regimens on time course and degree of therapeutic response. Pulsatile administration produced greater improvement than escalating levels.

Attention↗
PubMed2006

Sticks, stones, and hurtful words: relative effects of various forms of childhood maltreatment.

OBJECTIVE: Childhood maltreatment is an important psychiatric risk factor. Research has focused primarily on the effects of physical abuse, sexual abuse, or witnessing domestic violence. Parental verbal aggression has received little attention as a specific form of abuse. This study was designed to delineate the impact of parental verbal aggression, witnessing domestic violence, physical abuse, and sexual abuse, by themselves and in combination, on psychiatric symptoms. METHOD: Symptoms and exposure ratings were collected from 554 subjects 18-22 years of age (68% female) who responded to advertisements. The Verbal Abuse Questionnaire was used to assess exposure to parental verbal aggression. Outcome measures included dissociation and symptoms of "limbic irritability," depression, anxiety, and anger-hostility. Comparisons were made by using effect sizes. RESULTS: Verbal aggression was associated with moderate to large effects, comparable to those associated with witnessing domestic violence or nonfamilial sexual abuse and larger than those associated with familial physical abuse. Exposure to multiple forms of maltreatment had an effect size that was often greater than the component sum. Combined exposure to verbal abuse and witnessing domestic violence had a greater negative effect on some measures than exposure to familial sexual abuse. CONCLUSIONS: Parental verbal aggression was a potent form of maltreatment. Exposure to multiple forms of abuse was associated with very large effect sizes. Most maltreated children had been exposed to multiple types of abuse, and the number of different types is a critically important factor.

Adolescent↗
PubMed2006

Effects of childhood sexual abuse on neuropsychological and cognitive function in college women.

Twenty-six college women with a history of repeated childhood sexual abuse were recruited from the community and compared with 19 healthy female collegiate subjects on neurocognitive measures. Abused subjects showed increased response latency variability and diminished inhibitory capacity during a GO/NO-GO/STOP vigilance task. A strong association was found between duration of abuse and memory impairments. Math Scholastic Aptitude Test (SAT) scores were significantly lower in abused subjects when matched against comparison subjects and when compared to their own Verbal SAT scores. Childhood sexual abuse appears to be associated with a constellation of neuropsychological deficiencies even in a group of relatively healthy women.

Adolescent↗
PubMed2006

Neurobiological consequences of early stress and childhood maltreatment: are results from human and animal studies comparable?

Recent studies have reported an association between exposure to childhood abuse or neglect and alterations in brain structure or function. One limitation of these studies is that they are correlational and do not provide evidence of a cause-effect relationship. Preclinical studies on the effects of exposure to early life stress can demonstrate causality, and can enrich our understanding of the clinical research if we hypothesize that the consequences of early abuse are predominantly mediated through the induction of stress responses. Exposure to early abuse and early stress has each been associated with the emergence of epileptiform electroencephalogram (EEG) abnormalities, alterations in corpus callosum area, and reduced volume or synaptic density of the hippocampus. Further, there is evidence that different brain regions have unique periods when they are maximally sensitive to the effects of early stress. To date, preclinical studies have guided clinical investigations and will continue to provide important insight into studies on molecular mechanisms and gene-environment interactions.

Animals↗
PubMed2005

Objective measures of activity and attention in the differential diagnosis of psychiatric disorders of childhood.

Objective measures of attention, concentration, and motor activity can be used effectively in the assessment and differential diagnosis of bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD) in children. Children with BD were evaluated using actigraphy and the McLean Motion Analysis Test (M-MAT), and the results were compared with age- and gender-matched ADHD and normative data. Actigraphy indicated decreased sleep efficiency and duration with BD, with a longer latency and increased nocturnal activity. Using M-MAT clinicians were able to detect cognitive impairment and activation in children with mania, and worse-than-normal scores on measures of attention and increased levels of activity and impulsiveness in children with BD. Thus, objective measures of attention and activity can be of assistance in the differential diagnosis of ADHD and BD.

Adolescent↗
PubMed2004

Childhood neglect is associated with reduced corpus callosum area.

BACKGROUND: Childhood abuse has been associated with abnormalities in brain development, particularly corpus callosum (CC) morphology. The impact of neglect has not been assessed, though it is the most prevalent form of childhood maltreatment. METHODS: Regional CC area was measured from magnetic resonance imaging scans in 26 boys and 25 girls admitted for psychiatric evaluation (28 with abuse or neglect) and compared with CC area in 115 healthy control subjects. Data were analyzed by multivariate analysis of covariance, with age and midsagittal area as covariates. RESULTS: Total CC area of the abused/neglected patients was 17% smaller than in control subjects (p =.0001) and 11% smaller than in psychiatric patients who had not been abused or neglected (contrast group; p =.01). Control subjects and the contrast group did not differ in total CC area. Neglect was the strongest experiential factor and was associated with a 15%-18% reduction in CC regions 3, 4, 5, and 7 (all p <.02). In contrast, sexual abuse seemed to be the strongest factor associated with reduced CC size in girls. CONCLUSIONS: These data are consistent with animal research that demonstrated reduced CC size in nursery-reared compared with semi-naturally reared primates. Early experience might also affect the development of the human CC.

Adolescent↗
PubMed2004

Transient dopamine synthesis modulation in prefrontal cortex: in vitro studies.

The present study provides further evidence for transient D1 autoreceptor-like synthesis modulation in prefrontal cortex, but not striatum, of developing rats. DOPA accumulation was attenuated in a concentration-dependent manner in slices from the prefrontal cortex and striatum at 15 days of age by the partial D1 agonist SKF 38393 (0.01-10 microM) and the full D1 agonist SKF-81297 (0.01-10 microM) following NSD-1015; the response was no longer apparent by 40 days. Both agonists had greater potency in prefrontal cortex than striatum, and SKF-81297 exerted greater maximal inhibitory effects than SKF-38393. The inhibitory effects of both agonists were antagonized by pre-incubation with the D1 antagonist SCH-23390 in cortex, but not in striatum.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2004

Delayed effects of early stress on hippocampal development.

Early maternal separation has been shown in animal models to produce enduring morphological changes in the hippocampus and other brain structures, which may not become evident until adulthood. Postnatally, the trajectory of overproduction and pruning of axons, dendrites, synapses and receptors shapes the brain between puberty and adulthood. The objective of the study was to ascertain whether this normal trajectory was affected by repeated maternal separation. Rat pups were separated from their mother for 4 h a day between postnatal days 2 and 20 (ISO group), and compared to rat pups that remained with their mother in the animal facilities (AFR group) and were exposed to minimal handling. Immunoreactivity to synaptophysin was quantified in the hippocampus CA1 and CA3, amygdala, and prefrontal cortex using optical densitometry (OD) at 25, 40, 60, 80, and 100 days in male and female rats. Synaptophysin OD increased dramatically in CA1 and CA3 between 25 and 60 days in the AFR group and fell by the same degree between 60 and 100 days, showing the expected sequence of overproduction and pruning. No difference between groups in synaptophysin OD was observed at 25 and 40 days. However, at day 60 synaptophysin was 34-36% lower in CA1 and CA3 of the ISO group, and remained 24-26% lower at 100 days. Early isolation produced no enduring reduction in synaptophysin OD in the amygdala or prefrontal cortex. Overall, these results suggest that early maternal separation produced a regionally specific delayed effect on the structure of the hippocampus by attenuating rates of synaptic development.

Animals↗
PubMed2004

Novel strategy for the analysis of CPT data provides new insight into the effects of methylphenidate on attentional states in children with ADHD.

Continuous performance tasks (CPTs) provide a method for studying some components of attention, but do not take into account that attention fluctuates from moment to moment. To address this issue, CPT performance was classified into one of four states (on-task, impulsive, distracted, or randomly responding) every 30 seconds, based on commission and omission error rates. We evaluated this method on 60 boys (10.6 +/- 1.1 years) with attention-deficit hyperactivity disorder (ADHD)-Combined subtype, tested before and after a dose of methylphenidate (MPH, 0.4 mg/kg), and 8 unmedicated healthy control boys (11.3 +/- 2.0 years of age). Healthy controls were on-task during 82.4% of the 30-second epochs, and made an average of 5.4 attention shifts. In contrast, children with ADHD were only on-task during 42.6% of the epochs (p = 0.0006), and they made an average of 12.8 attention shifts (p = 0.00004). These state measures provided more robust indicators of the difference between children with ADHD and controls than did traditional CPT measures of error rates, latency, and variability. The new state measures were also more significantly affected by MPH. MPH produced a 77% increase in the percent of time children with ADHD spent on-task (p < 10(12)). Conversely, MPH reduced time spent in the distracted, impulsive, and random response states by 79%, 44.5%, and 69.2%, respectively (all p values < 0.0002). Unlike errors of omission and commission, which are highly correlated (r = 0.722, n = 60, p < 10(-11)), the percent of epochs spent in impulsive, distracted, and random response states were uncorrelated, and loaded onto discrete independent factors on principal component analysis. The level of activity during the CPT correlated with the degree of distraction, but not with the degree of impulsivity. Children with ADHD could be subtyped according to the nature of their attention performance problems, and these subtypes differed in levels of hyperactivity and degrees of response to MPH.

Attention↗
PubMed2003

Rate dependency revisited: understanding the effects of methylphenidate in children with attention deficit hyperactivity disorder.

Although stimulants are widely prescribed for the treatment of attention deficit hyperactivity disorder (ADHD), their calming effects are not easily understood. One hypothesis derived from preclinical studies is that stimulants exert "rate-dependent" effects that are inversely related in magnitude and direction to the baseline rate of activity or distraction. Previously, compelling support for this hypothesis has been lacking. We provide preliminary evidence that methylphenidate exerts rate-dependent behavioral effects in children with ADHD. Activity and attention were quantified in children with ADHD tested on placebo and different doses of methylphenidate using objective measures. Higher doses altered activity and attentiveness in a rate-dependent manner after correction for regression-to-the-mean artifacts. These findings illustrate a clear inverse association between symptom severity and degree of therapeutic response that is crucial for our understanding of stimulant effects and effective clinical treatment of ADHD.

Attention↗
PubMed2002

Differences in behavior and monoamine laterality following neonatal clomipramine treatment.

Postnatal treatment between 8 to 21 days of age with clomipramine (15 mg/kg, twice daily) produces an animal model that has many of the behavioral hallmarks of depression. In this study, we investigated the enduring behavioral and neurochemical effects of this early treatment in adult animals. Locomotor activity was increased in clomipramine-treated males, but not females, relative to vehicle-treated subjects. Increases in anxiety-like behavior in the elevated plus maze also were observed in clomipramine-exposed adults, but no sex differences were detected. Clomipramine-treated animals had shifts in the laterality of monoamines in limbic regions with lower serotonin levels on the right side while vehicle-treated animals had lower serotonin on the left side. The lateralization of dopamine content demonstrated the same pattern. This decline in monoaminergic content is consistent with clinical studies demonstrating decrements in serotonin as well as alterations in the lateralization of function in individuals with major depressive order.

Analysis of Variance↗
PubMed2002

Developmental neurobiology of childhood stress and trauma.

Severe early stress and maltreatment produces a cascade of events that have the potential to alter brain development. The first stage of the cascade involves the stress-induced programming of the glucocorticoid, noradrenergic, and vasopressin-oxytocin stress response systems to augment stress responses. These neurohumors then produce effects on neurogenesis, synaptic overproduction and pruning, and myelination during specific sensitive periods. Major consequences include reduced size of the mid-portions of the corpus callosum; attenuated development of the left neocortex, hippocampus, and amygdala along with abnormal frontotemporal electrical activity; and reduced functional activity of the cerebellar vermis. These alterations, in turn, provide the neurobiological framework through which early abuse increases the risk of developing post-traumatic stress disorder (PTSD), depression, symptoms of attention-deficit/hyperactivity, borderline personality disorder, dissociative identity disorder, and substance abuse.

Brain↗
PubMed2002

Pubertal changes in gonadal hormones do not underlie adolescent dopamine receptor overproduction.

Males, but not females, overproduce dopamine receptors in the striatum of rats across the periadolescent period followed by their elimination during young adulthood. In order to investigate the role that gonadal hormones play in this pubertal process, rats were castrated or ovariectomized at postnatal day (P) 28 when estrogen and testosterone levels are beginning to surge. Dopamine D1 and D2 striatal receptor density was then determined with autoradiography at P40 (adolescence) and P80 (young adulthood) to determine if either testosterone stimulates the overproduction of receptors in males or if estrogen inhibits this process in females. Neither castration nor ovariectomy altered dopamine receptor density, although enhanced testosterone levels increased D1 receptor binding 4.2% and 19.5% in males and females, respectively. The results of this study suggest that the endogenous rise in gonadal steroid hormones during puberty is not responsible for the overproduction of receptors in males or the lack of overproduction in females.

Aging↗
PubMed2002

Effects of methylphenidate on functional magnetic resonance relaxometry of the cerebellar vermis in boys with ADHD.

OBJECTIVE: The authors used functional magnetic resonance imaging (fMRI) to test the effects of methylphenidate on steady-state blood volume in the midline vermis of the cerebellum in boys with attention deficit hyperactivity disorder (ADHD). This region was selected as it has been observed to be significantly smaller in children with ADHD. Also, in preclinical studies, the vermis has been shown to modulate forebrain dopamine systems, to influence locomotor activity, and to contain a significant density of dopamine transporters. METHOD: T(2) relaxometry was used to indirectly assess blood volume in the cerebellum (hemispheres and midline vermis) of 10 boys with ADHD who were administered placebo or one of three different doses of methylphenidate continuously for 1 week. T(2) relaxation time values are inversely proportional to local cerebral blood volume. After each week of treatment, and within 1-3 hours of the boys' afternoon dose, testing for drug efficacy was performed by using objective measures of activity. RESULTS: Moderate and high doses of methylphenidate increased T(2) relaxation time in a rate-dependent manner-increasing T(2) relaxation time in the most active children with ADHD and reducing T(2) relaxation time in subjects with ADHD who were not objectively hyperactive. CONCLUSIONS: This preliminary study supports a role for the vermis in ADHD and suggests that further research is needed to clarify the relationship between vermal size, vermal blood flow, stimulant response, and the developmental pathophysiology of ADHD.

Attention↗
PubMed2002

Hand preference and length of psychiatric hospital stay by month of admission.

Length of psychiatric hospital stay is higher for patients admitted in the months of April and May. This effect was strongly associated with handedness and was greatest for left-handers. The duration of hospitalization of left-handed subjects admitted in April and May was, on average, 88.5% longer than for left-handed subjects admitted during any other period. In contrast, length of stay for right-handed patients differed by no more than 16% between any months compared.

Functional Laterality↗