Developmental changes in gamma-aminobutyric acid levels in attention-deficit/hyperactivity disorder.

While the neurobiological basis and developmental course of attention-deficit/hyperactivity disorder (ADHD) have not yet been fully established, an imbalance between inhibitory/excitatory neurotransmitters is thought to have an important role in the pathophysiology of ADHD. This study examined the changes in cerebral levels of GABA+, glutamate and glutamine in children and adults with ADHD using edited magnetic resonance spectroscopy. We studied 89 participants (16 children with ADHD, 19 control children, 16 adults with ADHD and 38 control adults) in a subcortical voxel (children and adults) and a frontal voxel (adults only). ADHD adults showed increased GABA+ levels relative to controls (P = 0.048), while ADHD children showed no difference in GABA+ in the subcortical voxel (P > 0.1), resulting in a significant age by disorder interaction (P = 0.026). Co-varying for age in an analysis of covariance model resulted in a nonsignificant age by disorder interaction (P = 0.06). Glutamine levels were increased in children with ADHD (P = 0.041), but there was no significant difference in adults (P > 0.1). Glutamate showed no difference between controls and ADHD patients but demonstrated a strong effect of age across both groups (P < 0.001). In conclusion, patients with ADHD show altered levels of GABA+ in a subcortical voxel which change with development. Further, we found increased glutamine levels in children with ADHD, but this difference normalized in adults. These observed imbalances in neurotransmitter levels are associated with ADHD symptomatology and lend new insight in the developmental trajectory and pathophysiology of ADHD.

Age dependent electroencephalographic changes in attention-deficit/hyperactivity disorder (ADHD).

OBJECTIVE: Objective biomarkers for attention-deficit/hyperactivity disorder (ADHD) could improve diagnostics or treatment monitoring of this psychiatric disorder. The resting electroencephalogram (EEG) provides non-invasive spectral markers of brain function and development. Their accuracy as ADHD markers is increasingly questioned but may improve with pattern classification. METHODS: This study provides an integrated analysis of ADHD and developmental effects in children and adults using regression analysis and support vector machine classification of spectral resting (eyes-closed) EEG biomarkers in order to clarify their diagnostic value. RESULTS: ADHD effects on EEG strongly depend on age and frequency. We observed typical non-linear developmental decreases in delta and theta power for both ADHD and control groups. However, for ADHD adults we found a slowing in alpha frequency combined with a higher power in alpha-1 (8-10Hz) and beta (13-30Hz). Support vector machine classification of ADHD adults versus controls yielded a notable cross validated sensitivity of 67% and specificity of 83% using power and central frequency from all frequency bands. ADHD children were not classified convincingly with these markers. CONCLUSIONS: Resting state electrophysiology is altered in ADHD, and these electrophysiological impairments persist into adulthood. SIGNIFICANCE: Spectral biomarkers may have both diagnostic and prognostic value.

Physiological and psychological individual differences influence resting brain function measured by ASL perfusion.

Effects of physiological and/or psychological inter-individual differences on the resting brain state have not been fully established. The present study investigated the effects of individual differences in basal autonomic tone and positive and negative personality dimensions on resting brain activity. Whole-brain resting cerebral perfusion images were acquired from 32 healthy subjects (16 males) using arterial spin labeling perfusion MRI. Neuroticism and extraversion were assessed with the Eysenck Personality Questionnaire-Revised. Resting autonomic activity was assessed using a validated measure of baseline cardiac vagal tone (CVT) in each individual. Potential associations between the perfusion data and individual CVT (27 subjects) and personality score (28 subjects) were tested at the level of voxel clusters by fitting a multiple regression model at each intracerebral voxel. Greater baseline perfusion in the dorsal anterior cingulate cortex (ACC) and cerebellum was associated with lower CVT. At a corrected significance threshold of p < 0.01, strong positive correlations were observed between extraversion and resting brain perfusion in the right caudate, brain stem, and cingulate gyrus. Significant negative correlations between neuroticism and regional cerebral perfusion were identified in the left amygdala, bilateral insula, ACC, and orbitofrontal cortex. These results suggest that individual autonomic tone and psychological variability influence resting brain activity in brain regions, previously shown to be associated with autonomic arousal (dorsal ACC) and personality traits (amygdala, caudate, etc.) during active task processing. The resting brain state may therefore need to be taken into account when interpreting the neurobiology of individual differences in structural and functional brain activity.

Coupling between resting cerebral perfusion and EEG.

While several studies have investigated interactions between the electroencephalography (EEG) and functional magnetic resonance imaging BOLD signal fluctuations, less is known about the associations between EEG oscillations and baseline brain haemodynamics, and few studies have examined the link between EEG power outside the alpha band and baseline perfusion. Here we compare whole-brain arterial spin labelling perfusion MRI and EEG in a group of healthy adults (n = 16, ten females, median age: 27 years, range 21-48) during an eyes closed rest condition. Correlations emerged between perfusion and global average EEG power in low (delta: 2-4 Hz and theta: 4-7 Hz), middle (alpha: 8-13 Hz), and high (beta: 13-30 Hz and gamma: 30-45 Hz) frequency bands in both cortical and sub-cortical regions. The correlations were predominately positive in middle and high-frequency bands, and negative in delta. In addition, central alpha frequency positively correlated with perfusion in a network of brain regions associated with the modulation of attention and preparedness for external input, and central theta frequency correlated negatively with a widespread network of cortical regions. These results indicate that the coupling between average EEG power/frequency and local cerebral blood flow varies in a frequency specific manner. Our results are consistent with longstanding concepts that decreasing EEG frequencies which in general map onto decreasing levels of activation.

Thalamic glutamate levels as a predictor of cortical response during executive functioning in subjects at high risk for psychosis.

CONTEXT: Alterations in glutamatergic neurotransmission and cerebral cortical dysfunction are thought to be central to the pathophysiology of psychosis, but the relationship between these 2 factors is unclear. OBJECTIVE: To investigate the relationship between brain glutamate levels and cortical response during executive functioning in people at high risk for psychosis (ie, with an at-risk mental state [ARMS]). DESIGN: Subjects were studied using functional magnetic resonance imaging while they performed a verbal fluency task, and proton magnetic resonance spectroscopy was used to measure their brain regional glutamate levels. SETTING: Maudsley Hospital, London, England. PATIENTS AND OTHER PARTICIPANTS: A total of 41 subjects: 24 subjects with an ARMS and 17 healthy volunteers (controls). MAIN OUTCOME MEASURES: Regional brain activation (blood oxygen level-dependent response); levels of glutamate in the anterior cingulate, left thalamus, and left hippocampus; and psychopathology ratings at the time of scanning. RESULTS: During the verbal fluency task, subjects with an ARMS showed greater activation than did controls in the middle frontal gyrus bilaterally. Thalamic glutamate levels were lower in the ARMS group than in control group. Within the ARMS group, thalamic glutamate levels were negatively associated with activation in the right dorsolateral prefrontal and left orbitofrontal cortex, but positively associated with activation in the right hippocampus and in the temporal cortex bilaterally. There was also a significant group difference in the relationship between cortical activation and thalamic glutamate levels, with the control group showing correlations in the opposite direction to those in the ARMS group in the prefrontal cortex and in the right hippocampus and superior temporal gyrus. CONCLUSIONS: Altered prefrontal, hippocampal, and temporal function in people with an ARMS is related to a reduction in thalamic glutamate levels, and this relationship is different from that in healthy controls.

Parametric mapping of the hepatic perfusion index with gadolinium-enhanced volumetric MRI.

The purpose of this study was to adapt the hepatic perfusion index (HPI) methodology previously developed for MRI to derive 3D parametric maps of HPI, and to investigate apparent differences in HPI maps between a group of colorectal cancer patients and controls. To achieve this, a new and simpler approach to HPI calculation which does not require measurements from the aorta or portal vein is introduced, and assessed with large liver regions of interest (ROIs) in patients and controls. Several example HPI maps showing localized variation are then presented. The subject group consisted of 12 patients with known colorectal metastases, and 13 control subjects referred for routine contrast-enhanced spine imaging with no history of neoplastic disease. HPI was evaluated from serial T1 volume acquisitions acquired over the course of a Gd-DTPA bolus injection. Regions of abnormal perfusion were visible on the HPI maps derived for the patient group, manifested as areas of locally increased HPI extending around the visible margins of known metastases evident on the conventional contrast-enhanced images. This method for MR voxel-based parametric mapping of HPI has the potential to demonstrate regional variations in perfusion at the segmental and subsegmental level.

Personality factors correlate with regional cerebral perfusion.

There is an increasing body of evidence pointing to a neurobiological basis of personality. The purpose of this study was to investigate the biological bases of the major dimensions of Eysenck's and Cloninger's models of personality using a noninvasive magnetic resonance perfusion imaging technique in 30 young, healthy subjects. An unbiased voxel-based analysis was used to identify regions where the regional perfusion demonstrated significant correlation with any of the personality dimensions. Highly significant positive correlations emerged between extraversion and perfusion in the basal ganglia, thalamus, inferior frontal gyrus and cerebellum and between novelty seeking and perfusion in the cerebellum, cuneus and thalamus. Strong negative correlations emerged between psychoticism and perfusion in the basal ganglia and thalamus and between harm avoidance and perfusion in the cerebellar vermis, cuneus and inferior frontal gyrus. These observations suggest that personality traits are strongly associated with resting cerebral perfusion in a variety of cortical and subcortical regions and provide further evidence for the hypothesized neurobiological basis of personality. These results may also have important implications for functional neuroimaging studies, which typically rely on the modulation of cerebral hemodynamics for detection of task-induced activation since personality effects may influence the intersubject variability for both task-related activity and resting cerebral perfusion. This technique also offers a novel approach for the exploration of the neurobiological correlates of human personality.

Comparison of the hepatic perfusion index measured with gadolinium-enhanced volumetric MRI in controls and in patients with colorectal cancer.

The aim of the study was to adapt the methodology established for dynamic CT measurements of the hepatic perfusion index (HPI) to MRI, and to assess the potential role of MRI measurements of the HPI in detecting regional alterations in liver perfusion between patients with colorectal liver metastases and normal controls. The HPI was evaluated from serial T(1) volume acquisitions acquired over the course of a Gd-DTPA bolus injection. Time-course data from regions of interest in the liver, spleen and aorta were used to calculate the HPI; and HPI data from control subjects were compared with data from patients with known colorectal metastases. Significant differences were found between the relative portal perfusion and hepatic perfusion indices calculated for the patient and control groups (p<0.005). These results suggest that hepatic perfusion indices can be derived using MRI-based methods, and that these perfusion indices are sensitive to differences in liver perfusion associated with established metastatic liver disease on imaging. This technique may contribute to the early detection of liver metastases, allowing early surgical intervention and improved patient survival.

Use of activated charcoal in a simulated poisoning with acetaminophen: a new loading dose for N-acetylcysteine?

STUDY OBJECTIVES: To investigate the ability of a supranormal dose of N-acetylcysteine to overcome the effects of activated charcoal on N-acetylcysteine bioavailability and to determine the effects of activated charcoal on serum acetaminophen levels. DESIGN, SETTING, AND PARTICIPANTS: Ten healthy adult volunteers participated in a controlled cross-over experiment. During phase I (control), subjects ingested 3 g acetaminophen, followed one hour later by the normal loading dose of N-acetylcysteine (140 mg/kg). During phase II (charcoal), subjects ingested 3 g acetaminophen, followed one hour later by 60 g activated charcoal and a supranormal loading dose of N-acetylcysteine (235 mg/kg). MAIN OUTCOME MEASURES: Serum levels of N-acetylcysteine were measured every 30 minutes for six hours. A serum acetaminophen level was measured at four hours. RESULTS: The area under the curve for N-acetylcysteine was significantly higher for phase II than phase I (P < .05, two-tailed paired t-test). Peak N-acetylcysteine and time to peak were not significantly different. The four-hour serum acetaminophen level was significantly lower for phase II than phase I (P < .05, two-tailed paired t-test). Diarrhea occurred during both phases, but N-acetylcysteine was otherwise well tolerated. CONCLUSION: These results suggest that activated charcoal can be used safely for victims of acetaminophen overdose. A beneficial effect in preventing acetaminophen absorption can be expected if it is given within one hour after ingestion. If N-acetylcysteine is needed because of a toxic serum acetaminophen level, bioavailability can be ensured by increasing the N-acetylcysteine loading dose from 140 mg/kg to 235 mg/kg.

Initial symptoms as predictors of esophageal injury in alkaline corrosive ingestions.

The predictive value of initial clinical evaluation in the management of alkaline corrosive ingestion remains unclear. This multicenter study was designed to determine if specific clinical signs and symptoms following ingestion of alkaline corrosives could predict significant esophageal injury. Alkaline corrosives were defined by a pH greater than or equal to 12. Signs and symptoms previously suggested as predictive of significant esophageal injury were documented on a standardized data form. Esophagoscopy reports were reviewed blinded to initial symptoms. Three hundred thirty-six alkaline-corrosive ingestions were analyzed. The mean number of symptoms reported in patients who did not have esophagoscopy was 1.2, in patients who had esophagoscopy was 3.0, and in patients that had visualized second or third degree esophageal burns was 4.8. Of 88 patients who had esophagoscopy, 63 (72%) had both the esophagoscopy report and initial symptom assessment available. Esophagoscopy was positive, defined as second or third degree esophageal burns, in 18 of 63 cases (29%). All patients with significant burns were symptomatic. No single or group of initially reported signs and symptoms could identify all patients with potentially serious esophageal burns.

Silver nitrate burns following treatment for umbilical granuloma.

Three infants treated for umbilical granuloma with silver nitrate suffered chemical burns to the periumbilical area which prompted visits to the emergency department. Treatment was conservative, and the outcome was good in all cases. We recommend caution when applying silver nitrate to the umbilicus, careful drying of the umbilical exudate to prevent spillage, and discussion with parents that burns may occur but apparently are not serious. The possibility of secondary infection is discussed.

Simulated acetaminophen overdose: pharmacokinetics and effectiveness of activated charcoal.

STUDY OBJECTIVE: To determine the absorption rate of a supratherapeutic dose of acetaminophen elixir and compare the effect of activated charcoal (AC) given at different time intervals on preventing acetaminophen absorption. DESIGN: Randomized, nonblinded, crossover controlled study. SETTING: A certified regional poison control center. PARTICIPANTS: Ten healthy, adult male volunteers from 21 to 39 years old. INTERVENTIONS: Each subject received 5 g acetaminophen (elixir) on four occasions: a control phase plus 30 g of AC administered 15, 30, or 120 minutes after acetaminophen. Serum acetaminophen levels were obtained during the control phase only, and 24-hour urine collections were obtained during all four phases. MEASUREMENTS AND MAIN RESULTS: The highest serum acetaminophen levels were measured 1.4 +/- 0.52 hours after ingestion, and absorption was 97% complete by a mean of 2.05 hours. The administration of AC at 15, 30, and 120 minutes after acetaminophen reduced urinary recovery of acetaminophen and metabolites by 48%, 44%, and 33%, respectively. CONCLUSION: AC significantly reduces urinary recovery but not absorption of acetaminophen when administered two hours after acetaminophen elixir.

Publication of presented abstracts at annual scientific meetings: a measure of quality?

One measure of the quality of research presented at the annual scientific meeting is publication of the data presented in a peer review journal. This allows for a more rigorous review of design, methodology and conclusions. To determine the rate of subsequent publication, MEDLARS searches were performed on the 269 presented abstracts at the 1984 and 1986 meetings of the American Association of Poison Control Centers, The American Academy of Clinical Toxicology, The American Board of Medical Toxicology and the Canadian Association of Poison Control Centers. Of the 296 presented abstracts, 134 (49.8%) were published. There was no difference in the eventual publication rate between the 1984 and 1986 meeting. There were 38 non-reviewed symposia publications and 96 peer-reviewed articles. Publications of 35.7% of presented abstracts in peer review journals compares poorly with the percentage of peer-reviewed publication from other scientific meetings. If publication in a peer-review journal is important, steps should be taken to improve the percentage of presented abstracts that are accepted by peer-review journals.

Assessment of management guidelines. Acute iron ingestion.

A review of 339 treated acute iron ingestions was conducted to define treatment guidelines better. According to the poison center protocol, ingestions of 20-40 mg/kg of elemental iron required only home treatment, and ingestions of greater than or equal to 40 mg/kg required hospital referral. Gastrointestinal symptoms developed in 23% of patients. There were no seriously ill patients. No serious toxicity developed in patients ingesting 40-60 mg/kg. In 199 cases in which the dose ingested was known, the mean dose was 39.5 mg/kg. The peak measured serum iron levels ranged from 12 to 539 micrograms/dl. In 129 cases with serum iron levels reported, increasing serum iron levels were associated with vomiting (p = 0.006). Of 88 patients who received deferoxamine, 14 had urine color change. Urine color change was associated with symptoms (p = 0.005) but not with iron dose or peak serum iron level. The poison center protocol was changed to home management for ingestions of 20-60 mg/kg unless significant symptoms developed and hospital referral for ingestions greater than or equal to 60 mg/kg.

Three fatal sodium azide poisonings.

We report 3 cases and review the published literature on sodium azide ingestion. A 38-year-old man intentionally ingested 2 tablespoonsful of sodium azide in water and developed seizures, coma, hypotension and fatal ventricular arrhythmias within 2 hours. A 33-year-old male ingested an unknown quantity of sodium azide. In the emergency department he was unconscious and underwent immediate intubation and gastric lavage. Nitrite therapy was instituted without improvement. He remained acidotic despite bicarbonate therapy and developed hypotension which was unresponsive to pressor agents. He died approximately 8 hours after admission despite resuscitative efforts. A 52-year-old male ingested 1.5 to 2g of sodium azide and survived for 40 hours. Nitrite therapy was ineffective. The role of sodium nitrite in treating sodium azide toxicity by producing methaemoglobin which complexes with azide is discussed.

Effects of magnesium citrate and clidinium bromide on the excretion of activated charcoal in normal subjects.

The efficacy of cathartics in shortening the gastrointestinal transit time of activate charcoal (AC) in the presence of drugs that alter gastrointestinal motility has not been determined. We evaluated the effects of magnesium citrate (MC) on the excretion of activated charcoal in healthy volunteers alone and with concurrent administration of the anticholinergic drug clidinium bromide. Forty subjects were randomized to clidinium bromide 5 mg or placebo capsule (PC), followed by activated charcoal 15 g and magnesium citrate or a placebo liquid (PL). The onset and duration of excretion of activated charcoal were noted. Mean onset times for activated charcoal were: group I (CB, MC) 4.5 +/- 2.1 h; group II (CB, PL) 17.0 +/- 10.0 h; group III (PC, MC) 6.3 +/- 5.8 h; and group IV (PC, PL) 20.6 +/- 8.4 h. The onset of excretion of activated charcoal was statistically different in both magnesium citrate groups as compared with the placebo liquid groups. The duration of activated charcoal in the stool was similar among the groups. The addition of clidinium bromide did not appear to affect gastrointestinal transit time. These results support previous studies of the effects of cathartics on the excretion of activated charcoal, and suggest that cathartic efficacy is not inhibited by anticholinergic drugs when used in therapeutic doses.

Occult bacteremia in children with simple febrile seizures.

The controversy surrounding the diagnostic workup for simple febrile seizures has centered around the lumbar puncture. This focus has obscured the potential importance of other tests. A retrospective study was performed to determine the frequency of occult bacteremia in simple febrile seizures. In a pediatric emergency department, we identified 115 cases of simple febrile seizures in children treated as outpatients. Blood cultures were performed in 93 (81%) of 115 patients; five (5.4%) were positive. Children were less likely to have blood cultures performed if they were older than 24 months or had a medical history of simple febrile seizures. However, neither age nor history of febrile seizures affected the risk of bacteremia. These data suggest that patients with simple febrile seizures are at approximately the same risk for bacteremia as children with fever alone. Patients with simple febrile seizures should be treated in the same manner as other patients of the same age with regard to the performance of blood cultures.

Lithium intoxication with acute renal failure and death.

A 65-year-old female presented with only gastrointestinal symptoms eight to ten hours after an acute ingestion of an unknown amount of lithium carbonate. The serum lithium concentration was 8.5 mEq/L. Forty-eight hours postingestion she developed acute renal failure, deteriorating mental status, and cardiovascular collapse. Despite both hemodialysis and peritoneal dialysis the patient died approximately four and one-half days after ingestion. A direct nephrotoxic effect of lithium is proposed.