Effects of changes in experimental design on PET studies of isometric force.

Based on single-cell recordings in primates, the relationship between neuronal activity and force magnitude is thought to be monotonic, at least for a subset of pyramidal cells in the motor cortex. Functional neuroimaging studies have also suggested a monotonic relationship between cerebral activation and force magnitude. In order to more precisely define this relationship and to characterize the activation pattern(s) associated with the modulation of static force, we studied 40 normal subjects using [(15)O]water PET and a simple visuomotor task-application of static force on a micro force sensor with the thumb and index finger of the right hand. When our experimental design did not produce the expected result (evidence of a relationship between cerebral activation and force magnitude in ten subjects), we made serial changes in the experimental protocol, including the addition of control (baseline) trials, and increased the number of subjects in an effort to increase our sensitivity to variations in force magnitude. We compared univariate and multivariate data-analytic strategies, but we relied on our multivariate results to elucidate the interaction of attentional and motor networks. We found that increasing the number of subjects from 10 to 20 resulted in an increase in statistical power and a more stable (i.e., more replicable) but qualitatively similar result, and that the inclusion of control trials in a 10-subject group did not enhance our ability to discern significant brain-behavior relationships. Our results suggest that sample sizes greater than 20 may be required to detect parametric variation in some instances and that failure to detect such variation may result from unanticipated neurobehavioral effects.

Multivariate predictive relationship between kinematic and functional activation patterns in a PET study of visuomotor learning.

Imaging studies of visuomotor learning have reported practice-related activation in brain regions mediating sensorimotor functions. However, development and testing of functional motor learning models, based on the relationship between imaging and behavioral measures, is complicated by the multidimensional nature of motoric control. In the present study, multivariate techniques were used to analyze [15O]water PET and kinematic correlates of learning in a visuomotor tracing task. Fourteen subjects traced a geometric form over a series of eight tracing trials, preceded and followed by baseline trials in which they passively viewed the geometric form. Simultaneous evaluation of multiple behavioral measures indicated that performance improvement was most strongly associated with a global performance measure and least strongly associated with measures of fine motor control. Results of three independent analytic techniques (i.e., intertrial correlation matrices, power function modeling, iterative canonical variate analysis) indicated that imaging and behavioral measures were most closely related on early learning trials. Performance improvement was associated with covarying increases in normalized activity among superior parietal, postcentral gyrus, and premotor regions and covarying decreases in normalized activity among cerebellar, inferior parietal, pallidal, and medial occipital regions. These findings suggest that performance improvement may be associated with increased activation in neural systems previously implicated in visually guided reaching and decreased activation in neural systems previously implicated in attentive visuospatial processing.

Neuroanatomic substrates of semantic memory impairment in Alzheimer's disease: patterns of functional MRI activation.

Impairment in semantic processing occurs early in Alzheimer's disease (AD) and differential impact on subtypes of semantic relations have been reported, yet there is little data on the neuroanatomic basis of these deficits. Patients with mild AD and healthy controls underwent 3 functional MRI auditory stimulation tasks requiring semantic or phonological decisions (match-mismatch) about word pairs (category-exemplar, category-function, pseudoword). Patients showed a significant performance deficit only on the exemplar task. On voxel-based fMRI activation analyses, controls showed a clear activation focus in the left superior temporal gyrus for the phonological task; patients showed additional foci in the left dorsolateral prefrontal and bilateral cingulate areas. On the semantic tasks, predominant activation foci were seen in the inferior and middle frontal gyrus (left greater than right) in both groups but patients showed additional activation suggesting compensatory recruitment of locally expanded foci and remote regions, for example, right frontal activation during the exemplar task. Covariance analyses indicated that exemplar task performance was strongly related to signal increase in bilateral medial prefrontal cortex. The authors conclude that fMRI can reveal similarities and differences in functional neuroanatomical processing of semantic and phonological information in mild AD compared to healthy elderly, and can help to bridge cognitive and neural investigations of the integrity of semantic networks in AD.

Neuropsychological correlates of methylphenidate treatment in adult ADHD with and without depression.

The purpose of this study was to characterize the neuropsychological profiles of adult patients with attention deficit hyperactivity disorder (ADHD) alone and ADHD with active comorbid depression, and to evaluate changes in the neuropsychological profile in these two groups following a trial of methylphenidate. Forty patients with ADHD were classified into two groups based on their affective status resulting in a group of 21 patients with ADHD alone and 19 patients with ADHD and active comorbid symptoms of depression (ADHD-D). All subjects received a comprehensive neuropsychological evaluation including measures of cognitive, motor and affective functioning before and after treatment. Fifteen normal controls were also assessed at a yoked time interval. At baseline, both patient groups showed impairment in verbal memory, motor and processing speed, visual scanning, and auditory and visual distractibility. Following treatment, both patient groups showed improvement across all neuropsychological measures while controls remained relatively stable over time. Improvement in neuropsychological test performance was not related to gender, affective status or referral source. Patients with active comorbid symptoms of depression show a similar neuropsychological profile and appear equally likely to benefit from methylphenidate intervention as patients with ADHD alone.

Effect of glucoprivation on self-stimulation rate-frequency functions.

In a series of two experiments using rats, the effect of glucoprivation, induced by 2-deoxy-D-glucose (2-DG) or insulin injections, on self-stimulation rate-frequency functions, was evaluated at two levels of current intensity. At the higher current intensity, neither insulin nor 2-DG produced a significant change in rate-frequency function parameters. At the lower current intensity, insulin suppressed asymptotic responding while 2-DG produced a lateral curve shift. Results of this study would argue that glucoprivation produces changes in self-stimulation at lateral hypothalamic electrodes that are: a) unrelated to the involvement of the neurons in stimulation-induced eating, b) are most notable when a smaller number of reward relevant neurons is stimulated, and c) can be differentially attributed to changes in motoric performance capacity during insulin tests and to changes in the reward value of stimulating current during 2-DG tests.

Changes in self-stimulation at stimulation-bound eating and drinking sites in the lateral hypothalamus during food or water deprivation, glucoprivation, and intracellular or extracellular dehydration.

These studies were designed to examine the effects of "hunger" induced by food deprivation, 2-deoxy-D-glucose (200 mg/kg), or insulin (2 U/kg) and "thirst" induced by water deprivation, sodium chloride (4 M), or polyethylene glycol (5 ml of 30% w/w) on lateral hypothalamic self-stimulation in 40 male Long-Evans rats. Changes in self-stimulation were evaluated at electrodes that produced stimulation-bound eating and/or drinking or neither behavior. Daily 30-min test sessions consisted of three 5-min periods of self-stimulation alternated with three 5-min periods when bar presses resulted in a 5-s time-out from experimenter-delivered stimulation (stimulation escape). Food deprivation significantly increased self-stimulation; insulin, 2-deoxy-D-glucose, and sodium chloride significantly suppressed self-stimulation; water deprivation mildly inhibited self-stimulation; and polyethylene glycol had no effect. This pattern of findings was noted at electrodes that did and those that did not elicit eating and/or drinking. These findings argue against the hypothesis that the magnitude of lateral hypothalamic self-stimulation is differentially and predictably controlled by specific drive mechanisms indexed by the consummatory behaviors also elicited by the stimulation.