Altered performance on an ocular fixation task in attention-deficit/hyperactivity disorder.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder without validated objective markers. Eye movement studies may be useful in providing objective criteria for characterizing the disorder. METHODS: We compared 53 children (29 girls) with ADHD to 44 healthy control children (18 girls) on a 21-sec fixation task. Large saccades (> 4 degrees ) away from the fixation point were analyzed. RESULTS: Children with ADHD made more large saccades that interrupted fixation than did control children (p =.001). Mean scores of the ADHD group did not change significantly with subsequent retesting on placebo (p =.11); however, there was poor intrasubject correlation (r =.16). CONCLUSIONS: Both boys and girls with ADHD made significantly more intrusive saccades during fixation than did control subjects, possibly reflecting intrinsic neurologic dysfunction; however, a probable "floor effect" obviates conclusions about the reliability of this measure.

Smooth pursuit eye-tracking impairment in childhood-onset psychotic disorders.

OBJECTIVE: Although childhood-onset schizophrenia is relatively rare, a sizable group of children with severe emotional disturbances have transient psychotic symptoms that fall outside of current syndrome boundaries. The relationship of this group of children to those with childhood-onset schizophrenia and other childhood psychiatric disorders is unclear. In this study, the authors compared smooth pursuit eye tracking, a biological trait marker associated with schizophrenia, of children and adolescents with psychotic disorder not otherwise specified to that of children with childhood-onset schizophrenia and healthy comparison subjects. METHOD: By means of infrared oculography, smooth pursuit eye movements during a 17 degrees /second visual pursuit task were quantitatively and qualitatively compared in 55 young adolescents (29 with childhood-onset schizophrenia and 26 with psychotic disorder not otherwise specified) and their respective independent healthy comparison groups (a total of 38 healthy subjects). RESULTS: Subjects with childhood-onset schizophrenia had qualitatively poorer eye tracking, higher root mean square error, lower gain, and a greater frequency of catch-up saccades than healthy children. Subjects with psychotic disorder not otherwise specified also had qualitatively poorer eye tracking, higher root mean square error, and lower gain than healthy children, but saccade frequency did not differ significantly. CONCLUSIONS: Children with childhood-onset schizophrenia exhibit a pattern of eye-tracking dysfunction similar to that reported for adult patients. Similar abnormalities were seen in the subjects with psychotic disorder not otherwise specified except that they did not exhibit a greater frequency of catch-up saccades. Prospective longitudinal neurobiological and clinical follow-up studies of both groups are currently underway to further validate the distinction between these two disorders. Also, family studies are planned to establish whether eye-tracking dysfunction represents a trait- or state-related phenomenon in subjects with psychotic disorder not otherwise specified.

Neuroimaging in alcoholism: ethanol and brain damage.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The co-chairs were Karl Mann and Ingrid Agartz. The presentations were (1) Neuropathological changes in alcohol-related brain damage, by Clive Harper; (2) Regional brain volumes including the hippocampus and monoamine metabolites in alcohol dependence, by Ingrid Agartz, Susan Shoaf, Robert R, Rawlings, Reza Momenan, and Daniel W Hommer; (3) Diffusion tensor abnormalities in imaging of white matter alcoholism, by Adolf Pfefferbaum and Edith V. Sullivan; (4) Use of functional MRI to evaluate brain activity during alcohol cue exposure in alcoholics: Relationship to craving, by Raymond F. Anton, David J. Drobes, and Mark S. George; and (5) mu-Opiate receptor availability in alcoholism: First results from a positron emission tomography study, by Karl Mann, Roland Bares, Hans-Juergen Machulla, Goetz Mundle, Matthias Reimold, and Andreas Heinz.

Executive function oculomotor tasks in girls with ADHD.

OBJECTIVE: To assess executive function in girls with attention-deficit/hyperactivity disorder (ADHD) using oculomotor tasks as possible trait markers for neurobiological studies. METHOD: Thirty-two girls aged 6 to 13 years with DSM-IV ADHD and 20 age-matched, normal control girls were tested on a variety of oculomotor tasks requiring attention, working memory, and response inhibition, which included smooth pursuit, delayed response, and go-no go tasks. RESULTS: Girls with ADHD performed the delayed response task correctly on 32% of trials as measured by number of memory-guided saccades, in contrast to 62% of trials for control subjects (p = .0009). Patients made twice as many commission errors to no go stimuli (p = .0001) and 3 times as many intrusion errors (saccades in the absence of go or no go stimuli; p = .004) during the go-no go task compared with controls. Smooth pursuit performance was statistically equivalent across subject groups. Repeated testing in a subgroup of 15 patients revealed substantial practice effects on go-no go performance. CONCLUSIONS: The data confirm that girls with ADHD exhibit impairments in executive function, as has been reported in boys, implying a similar pathophysiology of ADHD in both sexes. However, practice effects may limit the utility of the oculomotor go-no go task for some neurobiological studies.

Premorbid speech and language impairments in childhood-onset schizophrenia: association with risk factors.

OBJECTIVE: As both premorbid neurodevelopmental impairments and familial risk factors for schizophrenia are prominent in childhood-onset cases (with onset of psychosis by age 12), their relationship was examined. METHOD: Premorbid language, motor, and social impairments were assessed in a cohort of 49 patients with childhood-onset schizophrenia. Familial loading for schizophrenia spectrum disorders, familial eye-tracking dysfunction, and obstetrical complications were assessed without knowledge of premorbid abnormalities and were compared in the patients with and without developmental impairments. RESULTS: Over one-half of the patients in this group had developmental dysfunction in each domain assessed. The patients with premorbid speech and language impairments had higher familial loading scores for schizophrenia spectrum disorders and more obstetrical complications, and their relatives had worse smooth-pursuit eye movements. The boys had more premorbid motor abnormalities, but early language and social impairments did not differ significantly between genders. There were no other significant relationships between premorbid social or motor abnormalities and the risk factors assessed here. CONCLUSIONS: Premorbid developmental impairments are common in childhood-onset schizophrenia. The rates of three risk factors for schizophrenia (familial loading for schizophrenia spectrum disorders, familial eye-tracking dysfunction, and obstetrical complications) were increased for the probands with premorbid speech and language impairments, suggesting that the pathophysiology of schizophrenia involves the abnormal development of language-related brain regions.

Wisconsin Card Sorting Test performance following head injury: dorsolateral fronto-striatal circuit activity predicts perseveration.

The Wisconsin Card Sorting Test (WCST) has been argued to be a sensitive indicator of frontal lobe function. However, several recent studies have failed to find a consistent relationship between structural damage to this cortical area and perseveration on the test. In the present study, positron emission tomography (PET) imaging with 18F-fluorodeoxyglucose was used to examine the relationship of regional brain metabolism to perseverative responding on the WCST in patients with a history of closed-head injury. An inverse relationship was found between perseverative responses and metabolism in the right, but not the left, dorsolateral prefrontal cortex and caudate nucleus. Perseverative responding was not related to metabolism in several other regions of the frontal lobes and basal ganglia, including the putamen and the frontal poles bilaterally. These data suggest that the functional integrity of the right dorsolateral frontal-subcortical circuit is critical for WCST performance.

Hippocampal volume in patients with alcohol dependence.

BACKGROUND: Smaller hippocampal volumes have been reported in the brains of alcoholic patients than in those of healthy subjects, although it is unclear if the hippocampus is disproportionally smaller than the brain as a whole. There is evidence that alcoholic women are more susceptible than alcoholic men to liver and cardiac damage from alcohol. It is not known whether the hippocampi of the female brain are more vulnerable to alcohol. METHODS: We compared the hippocampal volumes in 52 hospitalized alcoholic men and women with those of 36 healthy nonalcoholic men and women. All subjects were between 27 and 53 years of age. The hippocampal volumes were measured from sagittal T-weighted high-resolution magnetic resonance images. RESULTS: The alcoholic women had less lifetime drinking and a later age at onset of heavy drinking than alcoholic men. Both alcoholic men and women had significantly smaller right hippocampi and larger cerebrospinal fluid volumes than healthy subjects of the same sex. Only among women were the left hippocampus and the nonhippocampal brain volume also significantly smaller. The proportion of hippocampal volume relative to the rest of the brain volume was the same in alcoholic patients and healthy subjects, in both men and women. The right hippocampus was larger than the left among all subjects. Women demonstrated larger hippocampal volumes relative to total brain volume than men. Psychiatric comorbidity, including posttraumatic stress disorder, did not affect hippocampal volume. CONCLUSIONS: In chronic alcoholism, the reduction of hippocampal volume is proportional to the reduction of the brain volume. Alcohol consumption should be accounted for in studies of hippocampal damage.

Functional imaging of craving.

To visualize brain activity associated with mental states, such as craving for alcohol and other drugs (AODs), researchers have begun to use functional imaging techniques. Three commonly used techniques are single photon emission computed tomography (SPECT), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI). Studies using these three approaches have been reviewed in order to evaluate the validity of a proposed model of the brain regions involved in alcoholism and the craving for alcohol. This model suggests a central role for a connected group of brain regions that include the basal ganglia, thalamus, and orbital cortex. A study using SPECT technology in alcoholics, however, found altered brain activity in only some of those regions during craving. Additional studies in alcoholics, as well as cocaine users, identified several other brain regions whose activities appeared to change in response to craving. These studies have led to the development of a revised model of brain regions involved in craving for AODs. Numerous questions remain, however, that must be answered before the brain areas involved in craving can be identified conclusively.

Statistical analysis of functional MRI data in the wavelet domain.

The use of the wavelet transform is explored for the detection of differences between brain functional magnetic resonance images (fMRI's) acquired under two different experimental conditions. The method benefits from the fact that a smooth and spatially localized signal can be represented by a small set of localized wavelet coefficients, while the power of white noise is uniformly spread throughout the wavelet space. Hence, a statistical procedure is developed that uses the imposed decomposition orthogonality to locate wavelet-space partitions with large signal-to-noise ratio (SNR), and subsequently restricts the testing for significant wavelet coefficients to these partitions. This results in a higher SNR and a smaller number of statistical tests, yielding a lower detection threshold compared to spatial-domain testing and, thus, a higher detection sensitivity without increasing type I errors. The multiresolution approach of the wavelet method is particularly suited to applications where the signal bandwidth and/or the characteristics of an imaging modality cannot be well specified. The proposed method was applied to compare two different fMRI acquisition modalities. Differences of the respective useful signal bandwidths could be clearly demonstrated; the estimated signal, due to the smoothness of the wavelet representation, yielded more compact regions of neuroactivity than standard spatial-domain testing.

A quantitative analysis of smooth pursuit eye tracking in monozygotic twins discordant for schizophrenia.

BACKGROUND: Previous studies of discordant monozygotic (MZ) twins have suggested that abnormal smooth pursuit eye tracking is an indicator of genetic liability for schizophrenia. We attempted to replicate this in a different sample of twins. METHODS: Probands from 12 sets of MZ twins discordant for schizophrenia who met DSM-III-R criteria for schizophrenia or schizoaffective disorder and their co-twins without psychiatric diagnosis (except 2 with a history of substance abuse) and 12 sets of normal control MZ twins. Psychiatric diagnosis was based on Structured Clinical Interview; monozygosity was based on analysis of 19 red blood cell antigens. Smooth pursuit eye movement gain (equal to the ratio of eye-target velocity) and numbers, amplitudes, and subtypes of saccadic eye movements were compared. Measures were derived from computer analysis of digitized infrared oculographic recordings of constant velocity (16.67 degrees per second) smooth pursuit eye tracking. RESULTS: Quantitative measures of eye tracking for the affected twin were inferior to those of the unaffected co-twin, with affected twins showing significant decreases in gain and significant increases in numbers and amplitudes of total and intrusive saccades. Moreover, whereas means for the group of affected twins differed significantly from those of normal controls on measures of gain and total saccades, means for the group of unaffected co-twins were well within the normal range. CONCLUSIONS: These data are consistent with the hypothesis that abnormal eye tracking is associated with the expression of illness, or phenotype, in schizophrenia, at least in this twin sample. The data raise questions regarding the use of eye tracking measurement for identifying putative gene carriers among at-risk relatives in genetic linkage studies of schizophrenia.

Smooth pursuit eye movements in childhood-onset schizophrenia: comparison with attention-deficit hyperactivity disorder and normal controls.

Abnormalities of the smooth pursuit eye movements of adults with schizophrenia have been well described. We examined smooth pursuit eye movements in schizophrenic children, contrasting them with normal and attention-deficit hyperactivity disorder (ADHD) subjects, to determine whether there is continuity of eye movement dysfunction between childhood- and adult-onset forms of schizophrenia. Seventeen schizophrenic children with onset of illness by age 12, 18 ADHD children, and 22 normal children were studied while engaged in a smooth pursuit eye tracking task. Eye tracking variables were compared across the three groups. Schizophrenic children exhibited significantly greater smooth pursuit impairments than either normal or ADHD subjects. Within the schizophrenic group, there were no significant relationships between eye tracking variables and clinical variables, or ventricular/brain ratio. Childhood-onset schizophrenia is associated with a similar pattern of smooth pursuit abnormalities to that seen in later-onset schizophrenia.

Blink rate in childhood-onset schizophrenia: comparison with normal and attention-deficit hyperactivity disorder controls.

Several lines of evidence have implicated central dopaminergic pathways in the modulation of blink rate. In the present study, blink rate during smooth pursuit was examined in 17 children with childhood-onset schizophrenia, on and off of clozapine, and compared to that of age-matched normal children and unmedicated children with attention-deficit hyperactivity disorder (ADHD). As has been observed in adolescent and adult schizophrenics, blink rate was significantly higher in schizophrenic children relative to normal and ADHD controls. Within the schizophrenic group, blink rate did not significantly change with the introduction of clozapine and was not related to clinical variables. Blink rate was positively correlated with deterioration in smooth pursuit in normal subjects.

Monitoring the source of memory in detoxified alcoholics.

The ability to monitor the source of remembered information and related reflective cognitive processes was examined in normal volunteers and detoxified alcoholics. Normal volunteers were very accurate judges of whether remembered events were presented as stimuli or were self-generated, even when memory was tested 2 days later. In contrast, a subgroup of otherwise cognitively unimpaired alcoholics demonstrated impairments in the ability to track the source of remembered knowledge and were also less able to inhibit intrusion errors in recalling information from memory. These findings provide preliminary evidence of an impairment in cognitive control functions in certain alcoholics. This conclusion is supported by associated findings indicating that, among alcoholics, performance on explicit memory tasks that required reflective cognitive operations were positively correlated with glucose utilization rates in left prefrontal, temporal, and posterior orbital frontal cortical regions.

Benzodiazepine sensitivity in panic disorder: effects of chronic alprazolam treatment.

The aim of the current study was to determine the degree to which patients with panic disorder develop tolerance to subjective and physiological effects of benzodiazepine after chronic treatment with alprazolam. Response to acute administration of diazepam was assessed in 19 panic disorder patients receiving chronic treatment with alprazolam and 23 untreated panic disorder patients. At baseline in the laboratory, the two groups did not differ in peak saccadic eye movement velocity, saccade latency, short-term memory, plasma cortisol and growth hormone concentrations, heart rate, and self-rated levels of sedation and anxiety. Compared with untreated patients, alprazolam-treated patients displayed significantly less diazepam-induced change in peak saccadic velocity, saccade latency, growth hormone secretion, memory, and self-rated levels of sedation. There was no difference between groups in diazepam effects on plasma cortisol concentrations or self-rated anxiety. Within alprazolam-treated patients, diazepam-induced slowing of peak saccade velocity was significantly inversely correlated with illness severity, as measured by reported panic attacks per week and severity of phobic avoidance, but not with alprazolam dose, blood level, or duration of treatment. Because the alprazolam-treated group reported more panic attacks per week than the untreated panic patients, treated patients were divided into those who were asymptomatic versus those with continuing panic attacks. The subgroup of nine alprazolam-treated subjects who were asymptomatic also showed significantly less diazepam effects than the group of untreated panic disorder patients, suggesting that overall group differences were at least partially attributable to the development of tolerance to selected benzodiazepine effects with chronic alprazolam treatment.

Saccadic eye movements in normal children from 8 to 15 years of age: a developmental study of visuospatial attention.

This cross-sectional study used saccadic eye movements, as measured by infrared occulography, to assess several aspects of visuospatial attention in normal children ages 8-15 years. Saccadic latency (a global measure of the ability to shift visuospatial attention), the ability to suppress extraneous saccades during fixation, and the ability to inhibit task-provoked anticipatory saccades all improve with age. However, the pattern of development differs for different tasks; saccadic latency shortens at a linear rate across the age range 8-15 years, while the capacity to inhibit anticipatory saccades matures by 12-13 years of age, and the ability to suppress saccades matures by 10 years of age. Analyses of age-related changes in oculomotor measures of attention may provide a novel approach in the study of children with attentional difficulties.

Quantitative effects of typical and atypical neuroleptics on smooth pursuit eye tracking in schizophrenia.

Smooth pursuit eye movement (SPEM) gain, total saccades, and subtypes of saccades were quantified from the visual pursuit tracking of 26 fluphenazine-treated patients with schizophrenia and 42 normal controls. Tracking was repeated in 16 patients who underwent a placebo-controlled, double-blind crossover comparison of fluphenazine and clozapine. Fluphenazine-treated patients showed significant reduction in SPEM gain and significant increases in both total, intrusive, and anticipatory saccades and in saccadic amplitude, when compared to controls. Clozapine significantly reduced SPEM gain and significantly increased total and catch-up saccades, when compared to placebo or fluphenazine. High amplitude of intrusive saccades in drug-free patients predicted poor response to clozapine, suggesting that intact frontal cortical function may enable optimal clozapine response.

Eye movement effects of diazepam in sons of alcoholic fathers and male control subjects.

Both animal and human studies suggest that the GABA-benzodiazepine receptor complex may be involved in the acute effects of ethanol, as well as the development of tolerance and dependence with chronic ethanol use. The current study was performed to assess sensitivity to benzodiazepines, and thus the functional sensitivity of the GABA-benzodiazepine receptor system, in subjects at high risk for alcoholism. Sons of alcoholic fathers (SOAs; n = 27) were compared with male controls without a family history of alcoholism (n = 23) in response to diazepam versus placebo. SOAs and controls received four logarithmically increasing doses of intravenous diazepam or placebo in randomized order on 2 days at least 1 week apart. Effects of diazepam were assessed using two eye movement tasks, peak saccadic eye movement velocity, and average smooth pursuit eye movement gain, which provide reliable, quantitative measures of benzodiazepine effects. In addition, memory, self-rated sedation, and pleasurable drug effects were measured. In comparison with control subjects, SOAs displayed significantly less diazepam effects on peak saccade velocity, average smooth pursuit gain, memory, and self-rated sedation, but significantly greater pleasurable drug effects. Differences in response to diazepam between SOAs and male controls may reflect altered functional sensitivity of the central GABA-benzodiazepine receptor system or a more general difference between groups in the effects of CNS active or sedating drugs.

A developmental study of smooth pursuit eye movements in normal children from 7 to 15 years of age.

OBJECTIVE: To examine age-related changes in smooth pursuit tracking. METHOD: Using infrared occulography, smooth pursuit eye movements are examined in 53 normal 7- to 15-year-old children during 6 degrees and 12 degrees/second visual pursuit. In addition to smooth pursuit gain and saccadic frequency, measures of mean amplitude per second are introduced to facilitate comparison across age and target speed. RESULTS: The 6 degrees/second task is found to be easier than the 12 degrees/second task. Age is correlated with smooth pursuit system performance but not saccadic system performance during 12 degrees/second pursuit. No measure correlates with age during 6 degrees/second pursuit. CONCLUSIONS: Eye movements improve as children age. The future use of smooth pursuit eye movements to study children and adolescents with and at risk for schizophrenia must control for developmental changes.

Personality and benzodiazepine sensitivity in anxious patients and control subjects.

Cloninger has recently proposed a model of personality variability that is based on three independent heritable traits of harm avoidance, novelty seeking, and reward dependence, each of which is thought to be mediated by a separate neurochemical and neuroanatomic mechanism. The current study tested hypotheses generated on the basis of this theory in anxious patients and control subjects. Eighteen patients with panic disorder, 12 patients with generalized anxiety disorder, and 21 control subjects underwent both personality testing and assessment of their sensitivity to diazepam, as measured by slowing of saccadic eye movement velocity. As expected, anxious patients displayed higher harm avoidance scores than controls. Although an inverse correlation between harm avoidance and benzodiazepine sensitivity was predicted, no relationship between these variables was found in any diagnostic group. However, a significant correlation was found between novelty-seeking scores and sensitivity to diazepam. This finding, although not predicted by Cloninger's theory, is consistent with prior preclinical and human studies.

Response to diazepam in sons of alcoholics.

Alcohol exerts several of its actions via the chloride channel associated with the central GABA-benzodiazepine receptor complex. To explore a possible role for this receptor complex in risk for alcoholism, and to determine whether risk for alcoholism is associated with risk for benzodiazepine abuse, the authors administered intravenous diazepam to 18 sons of male alcoholics (SOAs) and 18 control subjects. Four logarithmically increasing doses of diazepam and matched volumes of placebo were given in randomized order on separate days about 1 week apart. SOAs were significantly more likely than controls to report euphoric responses to diazepam. At some diazepam doses, SOAs were more likely to report feeling "high" and "intoxicated." SOAs and controls did not differ in feeling "drugged." SOAs and controls may differ in expectations regarding the subjective effects of drugs and/or in the function of the central GABA-benzodiazepine receptor complex. These findings also add further evidence for increased pleasurable effects, and thus possibly increased risk for benzodiazepine abuse, in a subgroup of SOAs.