Oculomotor inhibition in children with and without attention-deficit hyperactivity disorder (ADHD)

Summary. The aim of the present study was to distinguish between a general deficit in oculomotor control and a deficit restricted to inhibitory functions in children with attention deficit hyperactivity disorder (ADHD). In addition, we were interested in differentiating between a general inhibition deficit and deficient subfunctions of inhibition. We used a prosaccade task to measure general oculomotor abilities in 22 children with ADHD and in age- and gender-matched healthy controls. A fixation, an antisaccade and a countermanding saccade task were used to measure specific aspects of oculomotor inhibition. Two major results were obtained: First, our prosaccade task suggests similar saccadic response preparation and saccadic accuracy in the ADHD compared to the control children. Secondly, the fixation and the countermanding saccade task indicate deficits on measures of oculomotor inhibition in the ADHD group. While patients were specifically impaired in stopping an already initiated response or in suppressing exploratory saccades in a novel situation, inhibition of a prepotent response was not deficient. Our data thus indicate an underlying impairment in cognitive inhibition in ADHD that has been associated with prefrontal lobe functions. More specifically, as the anterior cingulate gyrus has been associated with the countermanding saccade task and group differences were most pronounced in this paradigm our data are in line with imaging data stressing the importance of this cortical structure in the pathophysiology of ADHD.     

Regional cerebral blood flow in children with attention deficit hyperactivity disorder: comparison before and after methylphenidate treatment

Differences in brain activity of children with attention deficit hyperactivity disorder (ADHD) have been compared to normal healthy controls, suggesting neural correlates of cognitive/behavioral symptoms. Symptoms are improved with methylphenidate treatment but limited sources can be cited to show how brain activity in ADHD is altered after pharmacologic treatment. We investigated how long-term oral medication of methylphenidate affects the resting regional cerebral blood flow (rCBF) in ADHD children, using single photon emission computerized tomography (SPECT). rCBF was decreased in the orbitofrontal cortex and middle temporal gyrus in the right hemisphere whereas it was increased in the dorsomedial prefrontal and somatosensory area bilaterally in drug-naive ADHD children compared to control child subjects. After treatment with methylphenidate, the extent of hyperperfusion in the somatosensory area was reduced and significant reduction of rCBF was found in the right striatum for the first time. Methylphenidate treatment also resulted in rCBF increase in superior prefrontal and reduction in ventral higher visual areas bilaterally. The results indicated that improving ADHD symptom after methylphenidate is associated with normalization of abnormally reduced orbitofrontal activity and abnormally increased somatosensory cortical activity. These changes were accompanied with reduced striatum activity lower than that of normal controls. These changes might be associated with improving ADHD to control attention and motor response to irrelevant environmental stimuli after methylphenidate treatment.     

The effect of ACTH on cerebral blood flow in children with intractable epilepsy

Cerebral blood flow was assessed by ultrasound in 12 children with intractable epilepsy who were treated with ACTH. The average maximal blood velocity (A/L) and end-diastolic blood velocity (d) of the internal carotid artery were measured, before, during and after ACTH therapy in each subject. The right and left mean A/L and d values were significantly decreased during ACTH therapy, and these values returned to the previous levels after the treatment. Cerebral function in children treated with ACTH may be affected by a decrease in cerebral blood flow.     

Attention and executive functions profile in drug naive ADHD subtypes

Attention deficit hyperactivity disorder (ADHD) has been associated with executive functioning and sustained and divided attention deficits. In order to clarify the questions on neurocognitive impairment in ADHD, we investigated the presence of specific executive functions (EFs) and attention deficit patterns in ADHD clinical subtypes. 50 patients with ADHD and 44 controls were evaluated. All subjects were boys and performed a clinical-psychopathological and neuropsychological battery. Five main domains of EFs and attention were studied. Executive functions-related neurocognitive abilities were used as control tasks. ADHD patients, inattentive and combined subtypes differ from controls on response inhibition, divided attention, phonological, and visual object working memory and on variability of reaction times measured with CPT. Comparison of ADHD subtypes, in five main domains of EFs, did not show evidence of different executive functioning profiles. Response inhibition can predict performance on working memory tests but it cannot predict performance on divided attention/set shifting and on sustained attention. ADHD boys exhibit a selective impairment on executive functions and attention tasks. These data suggest the involvement of partially independent neural circuits which control inhibition and divided attention in ADHD. Since right prefrontal cortex seems to be crucial in controlling response inhibition, while left dorsolateral prefrontal cortex seems important in modulating divided attention, these areas are deputated to be involved in the pathogenesis of neuropsychological deficits in ADHD subtypes. In addition, this study candidates the impairment in phonological and visual-object working memory as a possible neuropsychological trait in ADHD males with inattentive or combined subtypes.     

Dual effect of naloxone on blood platelet aggregation and cerebral blood flow in gerbils

The effect of naloxone on blood platelet aggregation and cerebral blood flow in gerbils was studied. Administration of naloxone in dose 1 mg/kg to intact gerbils resulted in a marked increase in platelet aggregability accompanied by 27% reduction in cerebral blood flow. Focal cerebral ischemic injury significantly enhanced platelet aggregatory response and treatment with naloxone was without any additional effect on platelet aggregation. Cerebral blood flow in ischemic hemisphere, however, increased following naloxone injection by 46%. In vitro naloxone in millimolar concentrations inhibited platelet aggregation in a dose-dependent way. Apparent decrease in fluorescence of platelet membranes tagged with fluorescence probe due to naloxone suggests conformational changes in platelet membrane as a primary mechanism for the antiaggregatory effect of naloxone in vitro.     

CBF changes in drug naive juvenile myoclonic epilepsy patients

Abstract Purpose The role of thalamus and brainstem in generalized epilepsy has been suggested in previous studies. The aim of the present study was to assess regional cerebral blood flow (rCBF) abnormality in juvenile myoclonic epilepsy (JME) patients. Methods ^99mTc-ethylcysteinate dimer brain single photon emission computed tomography (SPECT) was performed in 19 drug naive JME patients and 25 normal controls with the similar age and gender distribution. Differences of rCBF between a JME group and a normal control group were examined by the statistical parametric mapping of brain SPECT images using independent t test. The regression analyses in SPM were also performed between rCBF and the age of seizure onset or the disease duration in JME group. Results Compared to normal controls, the JME group showed a significant rCBF reduction in bilateral thalami, red nucleus, midbrain, pons, left hippocampus, and in the cerebelli (FDR corrected p < 0.01) whereas rCBF increase in the left superior frontal gyrus (uncorrected p < 0.001 but FDR corrected p > 0.05). Disease duration was negatively correlated with rCBF in bilateral frontal cortices, caudate nuclei, brainstem and cerebellar tonsils. Conclusions Our results suggest that abnormal neural networks in the thalamus, hippocampus, brainstem and cerebellum are associated with JME.     

Cerebral blood flow and metabolism in sleep

A review is presented of the electrical activity of the brain and its global and regional blood flow and metabolism in the different stages of sleep and in wakefulness in animals and humans. During slow-wave sleep (SWS), the blood flow and metabolism of the brain decrease slightly below the level of wakefulness. During rapid eye movement the activity of the brain increases above that of SWS and sometimes above that of wakefulness. Some studies suggest that both at sleep onset and at arousal the brain stem-cerebellar complex (BSC) may be activated before the cortex and the right hemisphere before the left. Variation of hemispheric dominance seems to be a phenomenon of both wakefulness and sleep.     

Regional cerebral blood flow in delirium patients

The purpose of the present paper was to determine the possible mechanism of delirium by using xenon-enhanced computed tomography to measure the regional cerebral blood flow (rCBF) of the patients both during delirium and after improvement from delirium. The rCBF measurements of the frontal, temporal and occipital cortex during delirium ranged from 31.4 to 39.6 mL/100 g per min; the rCBF of the thalamus and basal ganglia ranged from 47.5 to 52.4 mL/100 g per min. After recovery from delirium the rCBF of both areas returned to normal. The findings that reduced rCBF during delirium becomes normal once delirium improves suggest that a possible cause of delirium may be the cerebral hypoperfusion.     

Electrophysiological investigation of the effectiveness of methylphenidate in children with and without ADHD

Summary. The Continuous Performance Test (CPT) is an appropriate instrument for assessment of correlates at the brain electrical activity level of attention and response to stimulant medication. The aim of the study was to confirm at the electrophysiological level the clinical effectiveness of methylphenidate (MPH) in children with attention deficit / hyperactivity disorder (ADHD); to this end, a comparative study of hyperactive and healthy control children was undertaken, employing a modified CPT test. Twenty-one channel ERPs from 17 hyperactive boys, with and without MPH treatment, and from 20 healthy control children were analyzed with reference-independent techniques. The resulting quasi-stabile microstates correspond to the time ranges of the conventional ERP components P100, P200 and P300 (with the subcomponents P3a and P3b) and could be discriminated by means of data-based segmentation. The P3a amplitudes of the hyperactive children, in each case with and without MPH medication, were compared with those of healthy controls. P3a segment amplitudes were significantly lower in non-medicated ADHD patients than in healthy children, both following positive and inhibitory stimulus conditions. A significant medication effect was detected following MPH treatment: segment 3 amplitudes in MPH-treated hyperactive children were not significantly different from those of healthy controls. MPH exerts a highly potent effect on stimulus recognition and resulting consequences. Application of the CPT-OX enables the reliable measurement of electrophysiological correlates of the clinical effectiveness of MPH under different stimulus conditions. Received November 5, 2002; accepted January 27, 2003 Published online May 5, 2003 Authors' address: J. Seifert, M.D., Department of Child and Adolescent Psychiatry, University Hospital Würzburg, Füchsleinstrasse 15, D-97080 Wuerzburg, Germany, e-mail: kjp@nervenklinik.uni-wuerzburg.de     

Cerebral blood flow is an earlier indicator of perfusion abnormalities than cerebral blood volume in Alzheimer's disease

The purpose of this study was to elucidate whether cerebral blood flow (CBF) can better characterize perfusion abnormalities in predementia stages of Alzheimer''s disease (AD) than cerebral blood volume (CBV) and whether cortical atrophy is more associated with decreased CBV or with decreased CBF. We compared measurements of CBV, CBF, and mean cortical thickness obtained from magnetic resonance images in a group of healthy controls, patients with mild cognitive impairment (MCI) who converted to AD after 2 years of clinical follow-up (MCI-c), and patients with mild AD. A significant decrease in perfusion was detected in the parietal lobes of the MCI-c patients with CBF parametric maps but not with CBV maps. In the MCI-c group, a negative correlation between CBF values and cortical thickness in the right parahippocampal gyrus suggests an increase in CBF that depends on cortical atrophy in predementia stages of AD. Our study also suggests that CBF deficits appear before CBV deficits in the progression of AD, as CBV abnormalities were only detected at the AD stage, whereas CBF changes were already detected in the MCI stage. These results confirm the hypothesis that CBF is a more sensitive parameter than CBV for perfusion abnormalities in MCI-c patients.     

Regional cerebral blood flow abnormalities in chronic solvent abusers

This study aimed to reveal regional abnormalities of cerebral blood flow (CBF) and their relation to amotivational syndrome which causes poor social prognosis in solvent abusers Sixteen chronic solvent abusers (12 males and four females) along with five normal subjects underwent single photon emission computed tomography with N-isopropyl-p[123I]iodoamphetamine. The patients received a clinical evaluation with the Scale for the Assessment of Negative Symptoms. Using a semiquantitative method (normalized by the parietal cortex count), patients showed a statistically significant decrease in regional cerebral blood flow (rCBF) in the bilateral prefrontal cortices (P<0.01). In addition, the severity of hypoperfusion in the bilateral prefrontal cortices was related to the degree of severity of the avolition-apathy scale on SANS (left; P<0.05, right; P<0.01) even after excluding the effect of antipsychotics. These results suggest that rCBF abnormalities, especially in the prefrontal cortex, develop in chronic solvent abusers, and that this frontal hypoperfusion may be a biological basis of amotivational syndrome.     

Cerebral blood flow and metabolism in experimental hydrocephalus

Cerebral blood flow and metabolism were studied in experimental hydrocephalus which was produced by intracisternal injection of kaolin in cats, rabbits and rats. Measurements were carried out in varied stages of hydrocephalus. Local cerebral blood flow (I-CBF) was measured by the hydrogen clearance method. Assessment of cerebral metabolism was made biochemically in the brain tissues of various regions, including water content, Na, K, lactate, pyruvate, lipids, ATP, cyclic AMP, catecholamines and monoamine metabolites. Blood flow studies were performed in the cerebral cortex, periventricular white matter, thalamus and midbrain reticular formation in hydrocephalic cats. In all of these regions, I-CBF decreased to about half of the control in both acute and chronic stages of hydrocephalus. CO₂ reactivity to CBF was impaired only in the acute stage, while autoregulation of CBF was preserved in the hydrocephalic brain. Water content of the brain tissue increased temporarily only within the periventricular white matter of hydrocephalic rabbits concomitant with increase in Na and decrease in K. Transient increase in the lactate and lactate/pyruvate ratios was also observed in the frontal lobe tissue. In hydrocephalic rats, decrease in phospholipids and cholesterol was observed parallel with the degree of ventricular dilatation. ATP and cyclic AMP decreased biphasically in both acute and chronic stages. On the other hand, increase in concentrations of norepinephrine, dopamine, homovanillic acid, and 5-hydroxyindoleacetic acid became evident in the chronic stage of hydrocephalus. From the above results, it is concluded that the hydrocephalic brain sustained considerable disturbance of metabolism in all modalities in association with decreased blood flow, which is sufficient to explain the clinical symptoms of hydrocephalus.     

Cycloid psychosis: regional cerebral blood flow correlates of a psychotic episode.

Eight patients meeting Leonhard's criteria for cycloid psychosis were investigated on repeated occasions during a psychotic episode, with regional cerebral blood flow measurements and clinical ratings. The results showed that, at admission to the hospital, when the patients were clinically exacerbated, the mean hemispheric blood flow was significantly elevated compared with values from a normal control group. The hemispheric blood flow level covaried significantly with the degree of clinical symptoms, such that the more elevated the cortical blood flow was, the more behaviorally disturbed was the patient. At discharge from the hospital, the patients had no residual symptoms and the cortical blood flow was normal. These findings differ distinctly from those commonly made in other psychoses, such as schizophrenia.     

Effect of flunarizine on cerebral blood flow in baboons with or without focal cerebral ischaemia

In baboons with or without regional cerebral ischaemia (achieved by transorbital clip of the middle cerebral artery), cerebral blood flow (CBF) was measured using the intra-arterial Xenon-133 technique during steady-state, slight hypotension, and hypocapnia before and after administration of various doses of the calcium antagonist flunarizine (0.5 mg kg^–1, 1.0 mg kg^–1, or 10 μg kg^–1 min^–1 over 30 min). In normal baboons flunarizine did not alter CBF significantly, but at reduced blood pressure it increased CBF by 19.9% owing to exaggerated vasodilatory autoregulation. During hypocapnia flunarizine impaired the physiological reduction in CBF owing to reduced vasoconstriction. In baboons with cerebral ischaemia, CBF measurements were stable and comparable with those in a control group using an arterial clip unless flunarizine was added. In a group of five flunarizine-treated animals, mean CBF after positioning of the clip was higher than in the control group. However, the increase in mean CBF varied significantly between animals, indicating that a secondary reduction in CBF due to postischaemic pathophysiological processes was not prevented consistently.     

Rat models of dementia based on reductions in regional glucose metabolism,cerebral blood flow and cytochrome oxidase activity

Summary. Three models are described in rats which attempt to mimic morphological and behavioural pathology of Alzheimers dementia; intracerebroventricular injection of streptozotocin (STZ), permanent bilateral carotid artery occlusion (2VO) and brain mitochondrial cytochrome oxidase inhibition by sodium azide. Learning and memory are impaired within 4 weeks in all models. This probably involves a reduction in cortical and/or hippocampal cholinergic neurotransmission. STZ causes microglial activation and specific damage to myelinated tracts in the fornix through generation of oxidative stress, thereby disrupting connections between the septum and hippocampus. 2VO results in damage to myelin and CA1 cells in hippocampus and in abnormal processing of APP to -amyloid. It is not known if microglial activation and neuronal damage occur after sodium azide administration. Memory and learning can be improved in the STZ and 2VO models by estradiol, melatonin and cholinesterase inhibitors. Antioxidants and neuroprotective agents may also decrease memory deficits by preventing inflammation and neurodegeneration.     

Regional cerebral blood flow abnormalities in late-life depression:Relation to refractoriness and chronification

Abstract We examined patterns of regional cerebral blood flow (rCBF) abnormalities in 18 patients with major depressive disorder in late life using single photon emission computed tomography (SPECT) and (^99mTc-hexamethyl-propylenamine oxime (^99mTc-HMPAO). Compared with 13 age-matched controls, relative rCBF was significantly decreased bilaterally in the anterior cingulate gyrus, the prefrontal cortex, the temporal cortex, the parietal cortex, the hippocampus and the caudate nucleus. However, it was not correlated with the severity of depression or global cognitive dysfunction. In 10 patients with a prolonged depressive episode or prolonged residual symptoms (the refractory subgroup), robust and extensive decreases in rCBF were found compared with controls and the rCBF decreased significantly in the anterior cingulate gyrus and the prefrontal cortex compared with that in the non-refractory subgroup. In the non-refractory subgroup, rCBF decreased significandy in the caudate nucleus and tended to decrease in the anterior cingulate gyrus compared with controls. These findings indicate that dysfunction of the limbic system, the cerebral association cortex and the caudate nucleus may be implicated in late-life depression and that robust and extensive hypoperfusion, especially in the anterior cingulate and the prefrontal regions, may relate to refractoriness or chronification of depression.     

Acute changes in cerebral blood flow associated with marijuana smoking

Cerebral blood flow (CBF) was measured in experienced (ES) and inexperienced (IS) marijuana smokers with the 133xenon inhalation technique before and after smoking both a high-potency marijuana cigarette and a placebo marijuana cigarette. CBF was measured twice under resting conditions in a control group. Mood states before and after marijuana smoking were quantified with the Profile of Mood States (POMS). Analyses of POMS factors after smoking marijuana revealed IS had an increase in anxiety while ES had a decrease. IS also had a significant increase in depression and decrease in vigor, but neither variable changed in the ES. After marijuana, CBF decreased in IS, but in ES, it increased in comparison with the 2 control runs. In both IS and ES, CBF changes following placebo administration were similar to those associated with marijuana smoking. However, in IS, the marijuana-induced CBF decrease was significantly higher than that associated with placebo. There were no statistically significant differences between the CBF increase seen after placebo and marijuana in ES. Anxiety, anger, fatigue, confusion and depression had significant negative correlations with CBF while vigor correlated positively, but the anxiety factor was the only one to account for a significant percentage of the change (parital correlation) in hemispheric CBF.