Estimation from PET data of transient changes in dopamine concentration induced by alcohol: support for a non-parametric signal estimation method.

We previously developed a model-independent technique (non-parametric ntPET) for extracting the transient changes in neurotransmitter concentration from paired (rest & activation) PET studies with a receptor ligand. To provide support for our method, we introduced three hypotheses of validation based on work by Endres and Carson (1998 J. Cereb. Blood Flow Metab. 18 1196-210) and Yoder et al (2004 J. Nucl. Med. 45 903-11), and tested them on experimental data. All three hypotheses describe relationships between the estimated free (synaptic) dopamine curves (FDA(t)) and the change in binding potential (DeltaBP). The veracity of the FDA(t) curves recovered by nonparametric ntPET is supported when the data adhere to the following hypothesized behaviors: (1) DeltaBP should decline with increasing DA peak time, (2) DeltaBP should increase as the strength of the temporal correlation between FDA(t) and the free raclopride (FRAC(t)) curve increases, (3) DeltaBP should decline linearly with the effective weighted availability of the receptor sites. We analyzed regional brain data from 8 healthy subjects who received two [11C]raclopride scans: one at rest, and one during which unanticipated IV alcohol was administered to stimulate dopamine release. For several striatal regions, nonparametric ntPET was applied to recover FDA(t), and binding potential values were determined. Kendall rank-correlation analysis confirmed that the FDA(t) data followed the expected trends for all three validation hypotheses. Our findings lend credence to our model-independent estimates of FDA(t). Application of nonparametric ntPET may yield important insights into how alterations in timing of dopaminergic neurotransmission are involved in the pathologies of addiction and other psychiatric disorders.

A study of persistent post-concussion symptoms in mild head trauma using positron emission tomography.

BACKGROUND: Complaints of persistent cognitive deficits following mild head trauma are often uncorroborated by structural brain imaging and neuropsychological examination. OBJECTIVE: To investigate, using positron emission tomography (PET), the in vivo changes in regional cerebral uptake of 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) and regional cerebral blood flow (rCBF) in patients with persistent symptoms following mild head trauma. METHODS: Five patients with mild head trauma and five age and education matched healthy controls were imaged using FDG-PET to measure differences in resting regional cerebral glucose metabolism. Oxygen-15 labelled water (H(2)(15)O)-PET was also used to measure group differences in rCBF changes during a spatial working memory task. In addition, neuropsychological testing and self report of dysexecutive function and post-concussion symptoms were acquired to characterise the sample. RESULTS: There was no difference between patients and controls in normalised regional cerebral FDG uptake in the resting state in frontal and temporal regions selected a priori. However, during the spatial working memory task, patients had a smaller increase in rCBF than controls in the right prefrontal cortex. CONCLUSIONS: Persistent post-concussive symptoms may not be associated with resting state hypometabolism. A cognitive challenge may be necessary to detect cerebral changes associated with mild head trauma.

The neurobehavioural rating scale-revised: sensitivity and validity in closed head injury assessment.

OBJECTIVES: To investigate the factor structure and psychometric properties of the neurobehavioural rating scale-revised (NRS-R) and to determine its usefulness in clinical trials. METHODS: A consecutive series of patients sustaining severe closed head injury were evacuated to one of 11 large regional North American trauma centres and entered into a randomised, phase III, multicentre clinical trial investigating the therapeutic use of moderate hypothermia. Acute care personnel were blinded to outcome and outcome personnel were blinded to treatment condition. The Glasgow outcome scale (GOS) was the primary outcome measure. Secondary outcome measures included the disability rating scale (DRS) and the NRS-R. RESULTS: Exploratory factor analysis of NRS-R data collected at 6 months after injury (n=210) resulted in a five factor model including: (1) executive/cognition, (2) positive symptoms, (3) negative symptoms, (4) mood/affect, and (5) oral/motor. These factors showed acceptable internal consistency (0.62 to 0.88), low to moderate interfactor correlations (0.19 to 0.61), and discriminated well between GOS defined groups. Factor validity was demonstrated by significant correlations with specific neuropsychological domains. Significant change was measured from 3 to 6 months after injury for the total score (sum of all 29 item ratings) and all factor scores except mood/affect and positive symptoms. The total score and all factor scores correlated significantly with concurrent GOS and DRS scores. CONCLUSIONS: The NRS-R is well suited as a secondary outcome measure for clinical trials as its completion rate exceeds that of neuropsychological assessment and it provides important neurobehavioural information complementary to that provided by global outcome and neuropsychological measures.

Factor analysis of an outcome interview for use in clinical trials of traumatically brain-injured patients: a preliminary study.

OBJECTIVE: To study the factor structure, internal consistency, concurrent validity, and sensitivity to detect change in patient report of problems of a structured interview in relationship with accepted outcome measures. DESIGN: Outcome status of patients with severe traumatic brain injury participating in a randomized, phase III, multicenter clinical trial was assessed at 6 mo postinjury using the Glasgow Outcome Scale, the Disability Rating Scale, and the Severe Traumatic Brain Injury Outcome Interview. RESULTS: Exploratory factor analysis of the Severe Traumatic Brain Injury Outcome Interview produced a meaningful five-factor model: (1) activities of daily living; (2) cognitive; (3) affective; (4) behavioral; and (5) instrumental activities of daily living. The internal consistency of the factors ranged from moderate (0.61 instrumental activities of daily living) to high (0.94 activities of daily living); the interfactor correlations were moderate. The summed factor scores were significantly correlated with measures of global outcome: the Glasgow Outcome Scale (r = 0.66; P < 0.0001) and the Disability Rating Scale (r = 0.61; P < 0.0001). Patient report of cognitive problems correlated moderately with the neuropsychological tests. The summed factor scores were sensitive to change over time. CONCLUSIONS: Overall, the interview assessed the major important features of outcome pertinent to traumatic brain injury and demonstrated greater sensitivity to subtle changes over time than the unidimensional approaches, such as the Glasgow Outcome Scale and Disability Rating Scale.

Olfactory-evoked regional cerebral blood flow in Alzheimer's disease.

Olfaction is impaired in Alzheimer's disease (AD). It was hypothesized that AD would reduce olfactory-evoked perfusion in mesial temporal olfactory (piriform) cortex, where neuropathology begins. Seven AD patients and 8 elderly controls (ECs) underwent olfactory threshold and identification tests and olfactory stimulation during positron emission tomography. Odor identification was impaired in AD, but threshold was not. Olfactory stimulation in ECs activated right and left piriform areas and right anterior ventral temporal cortex. AD patients had less activation in right piriform and anterior ventral temporal cortex but not in the left piriform area. Although orbital cortex did not activate in ECs, there was a significant between-groups difference in this area. Right piriform activation correlated with odor identification. Impaired odor identification likely reflects sensory cortex dysfunction rather than cognitive impairment. Given olfactory bulb projections to the mesial temporal lobe, olfactory stimulation during functional imaging might detect early dysfunction in this region.

Comparison of rhyming and word generation with FMRI.

Functional magnetic resonance imaging (FMRI) has been successfully used to non-invasively map language function, but has several disadvantages. These include severe motion sensitivity, which limits overt verbal responses in behavioral paradigms, such as word generation. The lack of overt responses prevents behavioral validation, making data interpretation difficult. Our objective was to compare the FMRI activation patterns of a novel silent rhyme determination task requiring a non-verbal response, to covert word generation from visually presented letters. Five strongly right-handed subjects performed both tasks during multi-slice coronal echo-planar T2*-weighted FMRI. Single subject activation maps were generated for each task by correlation analysis of single pixel time series to a boxcar reference function. These maps for the two tasks were separately interpolated to 256(3), transformed into Talairach space, summed, and thresholded at t>6. Combined activation maps from both tasks showed similar robust perisylvian language area activation, including inferior frontal gyrus, posterior superior temporal lobe, and fusiform gyrus. Subjects performed well on the rhyming task, which activated left hemisphere cortical regions more selectively than the word generation task. The rhyming task showed less activation than the word generation task in areas typically not considered specifically related to language function, such as the dorsolateral prefrontal cortex and anterior cingulate. The rhyming task is a useful tool for brain mapping and clinical applications, potentially more specific to cortical language areas than verbal fluency.

Word rhyming as a probe of hemispheric language dominance with functional magnetic resonance imaging.

OBJECTIVE: The goal of this study was to create a probe of hemispheric dominance for language using functional magnetic resonance imaging. BACKGROUND: Surgical candidates for anterior temporal lobectomy often undergo the Wada test to determine language laterality. The Wada test is invasive and cannot localize intrahemispheric language areas when surgical resection encroaches on eloquent cortex. We report the results of a stimulation paradigm that activates regions involved in motor language, language phonology, and visual word form perception. METHOD: Five right-handed healthy subjects underwent blood oxygen level-dependent functional magnetic resonance imaging. Subjects alternately viewed consecutive word pairs, indicating when the words rhymed, and consecutive pairs of line arrays, indicating when the arrays matched by responding "Yes" or "No" using a button box. RESULTS: Subjects performed both tasks with equivalent accuracy. Compared with the nonverbal control task, word rhyming produced greater left-hemisphere activation than right-hemisphere activation. Foci of rhyme-related activation were found in the left Brodmann's area (BA) 44 (Broca's area), left dorsolateral prefrontal cortex (BA 9/46 and BA 8/9), left middle temporal gyrus (BA 22), and left fusiform gyrus (BA 37) in the posterior basal temporal lobe. Activation associated with the control task was present in the right parietal area and in right temporal and left parietal regions. CONCLUSIONS: Subvocal word rhyming activates dominant perisylvian cortical regions and may be useful for determining hemispheric language dominance and for functional mapping of language cortex.

A preliminary study of acute responses to clamped alcohol concentration and family history of alcoholism.

BACKGROUND: The clamping method of alcohol administration was combined with a battery of dependent measures of frontal lobe brain function, and a novel index of acute adaptation, in a preliminary study in order to explore the paradigm's sensitivity to a familial history of alcoholism (FHA). METHODS: Ten family history-positive (FHP) and 10 family history-negative (FHN) adult social drinkers of both genders underwent alcohol clamping. Twenty minutes after the start of an intravenous infusion of alcohol, the breath alcohol concentration was clamped at a target of 60+/-5 mg/dl for 150 min. Initial and adaptive responses to alcohol were assessed using scalar indices of change. One index assessed initial improvements or impairments in brain function after alcohol. The other index assessed acute adaptation (tolerance or sensitization) to alcohol while the brain's exposure to alcohol was held constant. The battery of dependent measures included subjective perceptions, neuropsychological tests, saccadic eye-movement tasks, and event-related potential (ERP) tasks. Effect sizes for FHA were estimated for 10 dependent variables that showed adequate baseline test-retest reliability (r>0.6). RESULTS: FHP subjects showed less intense initial responses to alcohol in subjective perceptions, but greater changes in the latency of volitional saccades and ERP P3 components than did the FHN controls. FHP subjects generally showed greater acute tolerance to alcohol than did controls, who showed more instances of acute sensitization at this moderate breath alcohol concentration. Effect sizes for FHA exceeded 0.4 in more than half of the indices. CONCLUSIONS: The BrAC clamping paradigm assesses initial and adaptive responses of a battery of behavioral and electrophysiological measures of frontal lobe function to ethanol that appear both reliable and sensitive to FHA.

Functional brain imaging in apraxia.

BACKGROUND: An extensive literature describes structural lesions in apraxia, but few studies have used functional neuroimaging. We used positron emission tomography (PET) to characterize relative cerebral glucose metabolism in a 65-year-old, right-handed woman with progressive decline in ability to manipulate objects, write, and articulate speech. OBJECTIVE: To characterize functional brain organization in apraxia. DESIGN AND METHODS: The patient underwent a neurological examination, neuropsychological testing, magnetic resonance imaging, and fludeoxyglucose F 18 PET. The patient's magnetic resonance image was coregistered to her PET image, which was compared with the PET images of 7 right-handed, healthy controls. Hemispheric regions of interest were normalized by calcrine cortex. RESULTS: Except for apraxia and mild grip weakness, results of the neurological examination were normal. There was ideomotor apraxia of both hands (command, imitation, and object) and buccofacial apraxia. The patient could recognize meaningful gestures performed by the examiner and discriminate between his accurate and awkward pantomime. The magnetic resonance image showed moderate generalized atrophy and mild ischemic changes. Positron emission tomographic scans showed abnormal fludeoxyglucose F 18 uptake in the posterior frontal, supplementary motor, and parietal regions, the left affected more than the right. Focal metabolic deficit was present in the angular gyrus, an area hypothesized to store conceptual knowledge of skilled movement. CONCLUSIONS: Greater parietal than frontal physiological dysfunction and preserved gesture recognition are not consistent with the theory that knowledge of limb praxis is stored in the dominant parietal cortex. Gesture comprehension may be more diffusely distributed.

Judgment pitfalls in estimating premorbid intellectual function.

Neuropsychological diagnosis first requires estimation of patients' premorbid cognitive ability. Although a number of methods have been proposed for this purpose, in practice there is little standardization. Often, clinical judgment and expert synthesis of multiple sources of information are prescribed to derive a premorbid estimate. There are, however, a number of systematic biases in human cognition that may lead clinicians to produce inaccurate estimates of premorbid function. This paper reviews the cognitive biases that are most likely to interfere with clinical judgment in this context. Given findings in the human judgment literature, actuarial strategies are recommended to avoid the contamination of cognitive bias.

Proactive inhibition and semantic organization: relationship with verbal memory in patients with schizophrenia.

Compared to other cognitive functions in schizophrenia, evidence suggests that verbal memory is particularly impaired. This study used the California Verbal Learning Test (CVLT) to examine proactive inhibition (PI) and semantic processing in verbal memory in 29 patients with schizophrenia and 29 healthy controls. Patients showed significantly less PI, but also did not organize (cluster) their recall according to semantic category. Controls and patients demonstrated small retroactive inhibition (RI) effects regardless of semantic content. Although both groups made similar types and numbers of free recall intrusion errors patients committed more phonemic and nonshared recognition errors. Results suggest that reduced semantic processing prevented build of PI, and contributes to defective memory in schizophrenia. The anatomic-physiologic abnormalities that underlie these findings may be particularly pronounced in prefrontal and temporal-parietal cortical areas.

Reading on the Wide Range Achievement Test-Revised and parental education as predictors of IQ: comparison with the Barona formula.

It is frequently necessary in research and clinical evaluations to obtain estimates of premorbid intelligence (IQ) which are separate from measured IQ. There is evidence that word reading may be useful in this aim. In order to determine the potential of the Wide Range Achievement Test-Revised (WRAT-R) reading subtest (READ) as an estimate of premorbid IQ, the present study examined the relationship between READ and IQ in healthy subjects. Consistent with other findings, READ accounted for a significant amount of variance in Verbal, Performance, and Full Scale IQ. Race and parental education, the latter being a variable not previously examined in this literature, accounted for incrementally valid variance in IQ beyond READ. The predictive power of these variables compares favorably with estimates made by the Barona IQ estimation formula, which uses only demographic information.