John L. Holt

Shared and distinct neurophysiological components of the digits forward and backward tasks as revealed by functional neuroimaging

The digits forward (DF) and backward (DB) tasks are widely used neuropsychological measures believed to tap overlapping systems of phonological processing and working memory. Studies of focal brain lesions have partially elucidated the brain regions essential for these tasks; however relatively little information exists on the underlying functional neuroanatomy in the intact brain. We therefore examined the shared and separate neural systems of these tasks in two positron emission tomography (PET) experiments. In Experiment 1, eight healthy participants performed verbal DF, DB, and a sensorimotor control task during measurement of regional cerebral blood flow (rCBF). DF and DB each activated frontal, parietal, and cerebellar regions as well as prominently activating medial occipital cortex. To eliminate possible visuospatial confounds, Experiment 2 replicated the first experiment in six additional healthy participants who were blindfolded during the study. No differences in activation were found between the two experimental groups. Combined data from both experiments demonstrate that DF and DB rely upon a largely overlapping functional neural system associated with working memory, most notably right dorsolateral prefrontal cortex (DLPFC) and bilateral inferior parietal lobule (IPL) as well as the anterior cingulate, a region associated with attentional effort. The degree of activation increased linearly with increasing task difficulty in DF. DB additionally recruited bilateral DLPFC, left IPL, and Brocas area. Medial occipital cortex (including higher and lower visual processing areas) was robustly activated in both DF and DB and could not be attributed to visual processing per se, suggesting a possible visual imagery strategy for these aural-verbal tasks.

226. Beyond hypofrontality in functional brain imaging of schizophrenia

patients are usually unable to perform as well as normal, healthy subjects (NV). In order to better characterize and represent this cognitivemaladaptationwe have studiedNV and SZ subjectsfollowing extensive(3 -5 thousandtrials) tonerecognitiontraining.The task consistedof a tone presentedevery 2 seconds;the subjectrecognized the tone as relativelyhighor lowin frequency.Thereferencestimulus was fixed but the test stimulusvariedduringthe trainingphase of the study. Sufficient disparity between the tones was used in order to generate an 80%accuracy score. A subgroupof SZ (n=12) was able to perform as well as the NV (n= 12) with respect to accuracy and response time (RT). Using positronemissiontomography(PET) and 15-Oxygen,water, blood flow methodology,we studied subjects recognizinglow disparity tones. The contrasting conditions showed similar shifts in brain activity when switchingfrom one conditionto another for NV and SZ. The correlationmaps for blood flow (rCBF) and RT, accurate trials only, differed significantlybetween groups. WhereasNVexhibitedgreaterrCBFfor faster RT in auditorycortices and cerebellum,SZ subjectsexhibitedrobustcorrelationsfor fast RT in frontal, cuneus and occipital regions. Multiple scan conditions permit analyses of brain changes between and within conditions, between and within groups.

3D arterial spin tagging studies of cognitive activation

Introduction Although single slice arterial spin tagging approaches have been used to study focal increases in cerebral blood flow (CBF) during cognitive tasks [ 11, they do not provide adequate coverage of the brain. The application of 3D arterial spin tagging approaches to cognitive activation studies has been restricted by sensitivity limitations. However, recent studies have shown that background suppressed multi-echo techniques can increase the sensitivity of 3D arterial spin tagging approaches [2,3]. The work presented here demonstrates that multi-echo background suppressed 3D arterial spin tagging approaches can be used to quantitate focal changes in cerebral blood tlow images during cognitive tasks.

206. Dorsal and ventral PFC responses to working memory differ in schizophrenia

establishing that a modified rodent spatial working memory task, the discrete-trial variable-delay alternation task, had important elements of human working memory paradigms. For example, performance remained submaximal and stable at second-long retention intervals, was dependent on retention interval and proactive inhibition, and on the integrity of the medial prefrontal cortex. Consistent with clinical findings, low dose amphetamine produced a delay-dependent improvement in performance while higher doses impaired performance at all retention intervals. D1 receptor blockade produced the predicted doseand delay-dependent impairment. D2 receptor blockade had no effect. Activation of metabotropic glutamate 2/3 (mGluR 2/3) receptors, which in the prefrontal cortex inhibits the slow asynchronous phase of glutamate release, also produced a delay-dependent impairment. Low doses of an AMPA/ kainate antagonist had similar effects as the mGluR2/3 agonist. In contrast, the detrimental effect of NMDA receptor blockade was independent of memory load, with the higher dose resulting in chance-level performance at all retention intervals. These findings suggest the following: (1) activation of NMDA receptors is necessary for the initiation of the mnemonic encoding, (2) during the retention phase, WM is maintained by slow components that include the asynchronous phase of glutamate release resulting in “sustained” (second-long) postsynaptic activation of glutamate receptors, and phasic release of dopamine resulting in activation of D1 receptors.

Multifiltering Signal Detection and Statistical Power in Brain Activation Studies

Varying levels of image smoothing in relation to experimental effect size was assessed by computing voxel-based statistical power estimates on brain positron emission tomography (PET) activation data measured in subjects during the Wisconsin card sorting task. Forty normal subjects underwent regional cerebral blood flow measurements using [15O]water PET. In general, the amount of smoothing necessary to achieve maximal power varied widely, but systematically, across the brain, tending to follow known neuroanatomical constraints, such as the juxtaposition of functionally reactive brain tissue and vasculature as well as other natural boundaries. However, statistical power was more readily improved as sample size increased in all brain areas. Variations in the optimum filter size across the brain suggest that neuroanatomical structure should be carefully considered in the selection of filter size, but also indicate that the best way to improve the reliability of findings is with increased sample size.