In-vivo imaging of grey and white matter neuroinflammation in Alzheimer's disease: a positron emission tomography study with a novel radioligand, [18F]-FEPPA.

Our primary aim was to compare neuroinflammation in cognitively intact control subjects and patients with Alzheimer's disease (AD) by using positron emission tomography (PET) with translocator protein 18 kDa (TSPO)-specific radioligand [(18)F]-FEPPA. [(18)F]-FEPPA PET scans were acquired on a high-resolution research tomograph in 21 patients with AD (47- 81 years) and 21 control subjects (49-82 years). They were analyzed by using a 2-tissue compartment model with arterial plasma input function. Differences in neuroinflammation, indexed as [(18)F]-FEPPA binding were compared, adjusting for differences in binding affinity class as determined by a single polymorphism in the TSPO gene (rs6971). In grey matter areas, [(18)F]-FEPPA was significantly higher in AD compared with healthy control subjects. Large increases were seen in the hippocampus, prefrontal, temporal, parietal and occipital cortex (average Cohen's d= 0.89). Voxel-based analyses confirmed significant clusters of neuroinflammation in the frontal, temporal and parietal cortex in patients with AD. In white matter, [(18)F]-FEPPA binding was elevated in the posterior limb of the internal capsule, and the cingulum bundle. Higher neuroinflammation in the parietal cortex (r= -0.7, P= 0.005), and posterior limb of the internal capsule (r= -0.8, P=0.001) was associated with poorer visuospatial function. In addition, a higher [(18)F]-FEPPA binding in the posterior limb of the internal capsule was associated with a greater impairment in language ability (r= -0.7, P=0.004). Elevated neuroinflammation can be detected in AD patients throughout the brain grey and white matter by using [(18)F]-FEPPA PET. Our results also suggest that neuroinflammation is associated with some cognitive deficits.

The SORL1 gene and convergent neural risk for Alzheimer's disease across the human lifespan.

Prior to intervention trials in individuals genetically at-risk for late-onset Alzheimer's disease, critical first steps are identifying where (neuroanatomic effects), when (timepoint in the lifespan) and how (gene expression and neuropathology) Alzheimer's risk genes impact the brain. We hypothesized that variants in the sortilin-like receptor (SORL1) gene would affect multiple Alzheimer's phenotypes before the clinical onset of symptoms. Four independent samples were analyzed to determine effects of SORL1 genetic risk variants across the lifespan at multiple phenotypic levels: (1) microstructural integrity of white matter using diffusion tensor imaging in two healthy control samples (n=118, age 18-86; n=68, age 8-40); (2) gene expression using the Braincloud postmortem healthy control sample (n=269, age 0-92) and (3) Alzheimer's neuropathology (amyloid plaques and tau tangles) using a postmortem sample of healthy, mild cognitive impairment (MCI) and Alzheimer's individuals (n=710, age 66-108). SORL1 risk variants predicted lower white matter fractional anisotropy in an age-independent manner in fronto-temporal white matter tracts in both samples at 5% family-wise error-corrected thresholds. SORL1 risk variants also predicted decreased SORL1 mRNA expression, most prominently during childhood and adolescence, and significantly predicted increases in amyloid pathology in postmortem brain. Importantly, the effects of SORL1 variation on both white matter microstructure and gene expression were observed during neurodevelopmental phases of the human lifespan. Further, the neuropathological mechanism of risk appears to primarily involve amyloidogenic pathways. Interventions targeted toward the SORL1 amyloid risk pathway may be of greatest value during early phases of the lifespan.

Lesion Explorer: a comprehensive segmentation and parcellation package to obtain regional volumetrics for subcortical hyperintensities and intracranial tissue.

Subcortical hyperintensities (SH) are a commonly observed phenomenon on MRI of the aging brain (Kertesz et al., 1988). Conflicting behavioral, cognitive and pathological associations reported in the literature underline the need to develop an intracranial volumetric analysis technique to elucidate pathophysiological origins of SH in Alzheimer's disease (AD), vascular cognitive impairment (VCI) and normal aging (De Leeuw et al., 2001; Mayer and Kier, 1991; Pantoni and Garcia, 1997; Sachdev et al., 2008). The challenge is to develop processing tools that effectively and reliably quantify subcortical small vessel disease in the context of brain tissue compartments. Segmentation and brain region parcellation should account for SH subtypes which are often classified as: periventricular (pvSH) and deep white (dwSH), incidental white matter disease or lacunar infarcts and Virchow-Robin spaces. Lesion Explorer (LE) was developed as the final component of a comprehensive volumetric segmentation and parcellation image processing stream built upon previously published methods (Dade et al., 2004; Kovacevic et al., 2002). Inter-rater and inter-method reliability was accomplished both globally and regionally. Volumetric analysis showed high inter-rater reliability both globally (ICC=.99) and regionally (ICC=.98). Pixel-wise spatial congruence was also high (SI=.97). Whole brain pvSH volumes yielded high inter-rater reliability (ICC=.99). Volumetric analysis against an alternative kNN segmentation revealed high inter-method reliability (ICC=.97). Comparison with visual rating scales showed high significant correlations (ARWMC: r=.86; CHIPS: r=.87). The pipeline yields a comprehensive and reliable individualized volumetric profile for subcortical vasculopathy that includes regionalized (26 brain regions) measures for: GM, WM, sCSF, vCSF, lacunar and non-lacunar pvSH and dwSH.

Diffusion tensor imaging abnormalities in depressed multiple sclerosis patients.

Depression is common in patients with multiple sclerosis, but to date no studies have explored diffusion tensor imaging indices associated with mood change. This study aimed to determine cerebral correlates of depression in multiple sclerosis patients using diffusion tensor imaging. Sixty-two subjects with multiple sclerosis were assessed for depression with the Beck Depression Inventory (BDI-II). All subjects underwent magnetic resonance imaging. Whole brain and regional volumes were calculated for lesions (hyper/hypointense) and normal-appearing white and grey matter. Fractional anisotropy and mean diffusivity were calculated for each brain region. Magnetic resonance imaging comparisons were undertaken between depressed (Beck Depression Inventory > or = 19) and non-depressed subjects. Depressed subjects (n = 30) had a higher hypointense lesion volume in the right medial inferior frontal region, a smaller normal-appearing white matter volume in the left superior frontal region, and lower fractional anisotropy and higher mean diffusivity in the left anterior temporal normal-appearing white matter and normal-appearing grey matter regions, respectively. Depressed subjects also had higher mean diffusivity in right inferior frontal hyperintense lesions. Magnetic resonance imaging variables contributed to 43% of the depression variance. We conclude that the presence of more marked diffusion tensor imaging abnormalities in the normal-appearing white matter and normal-appearing grey matter of depressed subjects highlights the importance of more subtle measures of structural brain change in the pathogenesis of depression.

A SPECT study of sleep disturbance and Alzheimer's disease.

BACKGROUND/AIMS: This study aimed to investigate the possible association of regional cerebral perfusion and sleep loss in Alzheimer's disease (AD). METHODS: 55 AD patients were characterized as having (SL) or not having (NSL) nocturnal sleep loss based on standard AD scales assessing sleep over the previous 4 weeks. (99m)Tc-ethylcysteinate dimer SPECT scans were performed in a relaxed, wakeful state. Whole-brain analysis using Statistical Parametrical Mapping (SPM5) was performed to compare perfusion across groups. In addition, the AD groups were compared to normal control (NC) subjects of comparable age and gender to provide a context for interpretation of findings. RESULTS: SPM analysis showed increased perfusion in the right middle frontal gyrus (R-MFG, Brodman area 9, p = 0.016, familywise-error-corrected) in SL versus NSL patients. Comparison with NC subjects confirmed that perfusion in the R-MFG among SL patients did not exceed that found in NCs (relative rather than absolute hyperperfusion). CONCLUSIONS: In this sample of mild-to-moderate AD patients, relative hyperperfusion in the R-MFG is associated with reports of SL. This region may play a role in regulating sleep.

A quantitative evaluation of human coordination interfaces for computer assisted surgery.

Computer assisted surgery (CAS) for tumor resection can assist the surgeon in locating the tumor margin accurately via some form of guidance method. A wide array of guidance methods can be considered, including model-based visual representations, symbolic graphical interfaces, and those based on other sensory cues such as sound. Given the variety of these guidance methods, it becomes increasingly important to test and analyze guidance methods for CAS in a quantitative and context-dependent manner to determine which is most suitable for a given surgical task. In this paper, we present a novel experimental methodology and analysis framework to test candidate guidance methods for CAS. Different viewpoints and stereographic, symbolic and auditory cues were tested in isolation or in combination in a set of virtual surgery experiments. A total of 28 participants were asked to circumscribe a virtual tumor with a magnetically tracked scalpel while measuring the surgical trajectory. This allowed measurement of surgical accuracy, speed, and the frequency with which the tumor margin was intersected, and enabled a quantitative comparison of guidance approaches. This study demonstrated that adding sound to pictorial guidance methods consistently improved accuracy, speed and margin intersection of the virtual surgery. However, the use of stereovision showed less benefit than expected. While guidance based on a combination of symbolic and pictorial cues enhanced accuracy, we found that speed could be substantially impaired. These studies demonstrate that optimal guidance combinations exist which would not be apparent by studying individual guidance methods in isolation. Our findings suggest that care is needed when using expensive and sometimes cumbersome virtual visualization technologies for CAS, and that simpler, non-stereo presentation may be sufficient for specific surgical tasks.

Semiautomatic brain region extraction: a method of parcellating brain regions from structural magnetic resonance images.

Structural MR imaging has become essential to the evaluation of regional brain changes in both healthy aging and disease-related processes. Several methods have been developed to measure structure size and regional brain volumes, but many of these methods involve substantial manual tracing and/or landmark identification. We present a new technique, semiautomatic brain region extraction (SABRE), for the rapid and reliable parcellation of cortical and subcortical brain regions. We combine the SABRE parcellation with tissue compartment segmentation [NeuroImage 17 (2002) 1087] to produce measures of gray matter (GM), white matter (WM), ventricular CSF, and sulcal CSF for 26 brain regions. Because SABRE restricts user input to a few easily identified landmarks, inter-rater reliability is high for all volumes, with all coefficients between 0.91 and 0.99. To assess construct validity, we contrasted SABRE-derived volumetric data from healthy young and older adults. Results from the SABRE parcellation and tissue segmentation showed significant differences in multiple brain regions in keeping with regional atrophy described in the literature by researchers using lengthy manual tracing methods. Our findings show that SABRE is a reliable semiautomatic method for assessing regional tissue volumes that provides significant timesavings over purely manual methods, yet maintains information about individual cortical landmarks.

Structural brain abnormalities in multiple sclerosis patients with major depression.

OBJECTIVE: To assess the association between major depression and structural brain abnormalities in patients with multiple sclerosis (MS). METHODS: Two groups of patients with clinically definite MS were studied: 21 with Diagnostic and Statistical Manual of Mental Disorders (4th ed.)-defined major depression and 19 without. The groups did not differ on demographic, disease, or cognitive measures. All subjects underwent brain MRI. Tissue segmentation and regional brain masking were applied to the MRI data. RESULTS: Compared with the euthymic subjects, those with major depression had a greater T2-weighted lesion volume (p = 0.003) and more extensive T1-weighted lesion volume in the left medial inferior prefrontal cortex (p = 0.01) and less gray matter volume (p = 0.01) and more CSF volume in the left anterior temporal region (p = 0.005). A logistic regression analysis identified two independent predictors of depression: left medial inferior prefrontal cortex T2 lesion volume and left anterior temporal CSF volume. These variables accounted for 42% of the depression variance score. CONCLUSION: Whereas both lesion burden and atrophy are important in the pathogenesis of depression in MS, psychosocial influences should also be considered.

Discrimination of single features and conjunctions by children.

Stimuli that are discriminated by a conjunction of features can show more rapid early processing in adults. To determine how this facilitation effect develops, the processing of visual features and their conjunction was examined in 7-12-year-old children. The children completed a series of tasks in which they made a target-non-target judgement as a function of shape only, colour only or shape and colour features, while event-related potentials were recorded. To assess early stages of feature processing the posteriorly distributed P1 and N1 were analysed. Attentional effects were seen for both components. P1 had a shorter latency and P1 and N1 had larger amplitudes to targets than non-targets. Task effects were driven by the conjunction task. P1 amplitude was largest, while N1 amplitude was smallest for the conjunction targets. In contrast to larger left-sided N1 in adults, N1 had a symmetrical distribution in the children. N1 latency was shortest for the conjunction targets in the 9-10-year olds and 11-12-year olds, demonstrating facilitation in children, but which continued to develop over the pre-teen years. These data underline the sensitivity of early stages of processing to both top-down modulations and the parallel binding of non-spatial features in young children. Furthermore, facilitation effects, increased speed of processing when features need to be conjoined, mature in mid-childhood, arguing against a hierarchical model of visual processing, and supporting a rapid, integrated facilitative model.

A multivariate, spatiotemporal analysis of electromagnetic time-frequency data of recognition memory.

Electromagnetic indices of "fast" (above 12 Hz) oscillating brain activity are much more likely to be considerably attenuated by time-averaging across multiple trials than "slow" (below 12 Hz) oscillating brain activity. To the extent that both types of oscillations represent the activity of temporally and topographically separable neural populations, time averaging can cause a loss of brain activity information that is important both conceptually and for multimodal integration with hemodynamic techniques. To address this issue for recognition memory, simultaneous electroencephalography (EEG) and whole-head magnetoencephalography (MEG) recordings of explicit word recognition from 11 healthy subjects were analyzed in two different ways. First, the time course of neural oscillations ranging from theta (4.5 Hz) to gamma (42 Hz) frequencies were identified using single-trial continuous wavelet transforms. Second, traditional analyses of amplitude variations of time-averaged EEG and MEG signals, event-related potentials (ERPs), and fields (ERFs) were performed and submitted to distributed source analyses. To identify data patterns that covaried with the difference between correctly recognized studied (old) words and correctly rejected nonstudied (new) words, a multivariate statistical tool, partial least squares (PLS), was applied to both types of analyses. The results show that ERPs and ERFs are mainly displaying those neural indices of recognition memory that oscillate in the theta (4.5-7.5 Hz), alpha (8-11.5), and to some extent in the beta1 (12-19.5 Hz) frequency range. The sources of the ERPs/ERFs were in good agreement with the topography of theta/alpha/beta 1 oscillations in being confined to the anterior temporal lobe at 400 ms and being distributed across temporal, parietal, and occipital areas between 500 and 700 ms. Gamma oscillations covaried either positively or negatively with theta/alpha/beta1 oscillations. A positive covariance, for instance, was detected over left anterior temporal sensors as early as 200-350 ms and is compatible with studies in rodents showing that gamma and theta oscillations emerge together out of the interaction of the hippocampus and the entorhinal and perirhinal cortices. Fast beta oscillations (20-29.5 Hz), on the other hand, did not strongly covary with slow oscillations and were likely to arise from neural populations not adequately represented in ERPs/ERFs. In summary, by providing a more comprehensive description of electromagnetic signals, time-frequency data are of potential benefit for integrating electrophysiological and hemodynamic indices of brain activity and also for integrating human and animal electrophysiology.

A reliable MR measurement of medial temporal lobe width from the Sunnybrook Dementia Study.

We studied the hippocampal angle and spatial relationships of medial temporal lobe (MTL) structures, using midbrain colliculi and inter-collicular sulcus (ICS) as landmarks, and measured MTL width on axial 3D-T1-weighted MRI at ICS level in 41 normal, aged participants. Mean hippocampal angle was 29 degrees (range 17-42 degrees ) caudal to the anterior-posterior commissure (AC-PC) line. The slice at the ICS, parallel to the long axis of the hippocampus, best revealed a longitudinal view of hippocampus and parahippocampal gyrus in 76% of participants, compared to only 7% when slices were 20 degrees caudal to orbitomeatal line (OML), an accepted technique used to examine MTL width in previous CT studies. The MTL width measured midway and at its thinnest between the anterior-posterior borders of the midbrain was highly reproducible (intraclass correlation coefficients >0.98) using these new methods. These simple decision rules, individualized orientation along the hippocampus and using a standardized landmark like the ICS, make these measures more comparable across subjects, and hence more useful in detecting and monitoring MTL atrophy in dementia.

A robust method for extraction and automatic segmentation of brain images.

A new protocol is introduced for brain extraction and automatic tissue segmentation of MR images. For the brain extraction algorithm, proton density and T2-weighted images are used to generate a brain mask encompassing the full intracranial cavity. Segmentation of brain tissues into gray matter (GM), white matter (WM), and cerebral spinal fluid (CSF) is accomplished on a T1-weighted image after applying the brain mask. The fully automatic segmentation algorithm is histogram-based and uses the Expectation Maximization algorithm to model a four-Gaussian mixture for both global and local histograms. The means of the local Gaussians for GM, WM, and CSF are used to set local thresholds for tissue classification. Reproducibility of the extraction procedure was excellent, with average variation in intracranial capacity (TIC) of 0.13 and 0.66% TIC in 12 healthy normal and 33 Alzheimer brains, respectively. Repeatability of the segmentation algorithm, tested on healthy normal images, indicated scan-rescan differences in global tissue volumes of less than 0.30% TIC. Reproducibility at the regional level was established by comparing segmentation results within the 12 major Talairach subdivisions. Accuracy of the algorithm was tested on a digital brain phantom, and errors were less than 1% of the phantom volume. Maximal Type I and Type II classification errors were low, ranging between 2.2 and 4.3% of phantom volume. The algorithm was also insensitive to variation in parameter initialization values. The protocol is robust, fast, and its success in segmenting normal as well as diseased brains makes it an attractive clinical application.

Spatiotemporal analysis of experimental differences in event-related potential data with partial least squares.

One challenge in the analysis of event-related potentials (ERPs) is to identify task-related differences in scalp topography. The multivariate Partial Least Squares (PLS) analysis was used to identify the spatiotemporal distribution of ERP differences related to experimental manipulations. Two simulations included latency shifts and amplitude changes at peaks with temporal overlap. PLS identified effects only at modeled timepoints and electrodes. In contrast, principal components analysis identified differences at most timepoints. We also demonstrated that PLS identified combinations of waveform differences, not isolated sources. ERP components in an auditory oddball task were also assessed with PLS. The primary distinction was between ERPs on hit and correct rejection trials, expressed at multiple timepoints and electrodes. PLS provides a mechanism to describe experimental differences in ERP waveforms, simultaneously across the head.

Piracetam therapy does not enhance cognitive functioning in children with down syndrome.

BACKGROUND: Piracetam is widely used as a purported means of improving cognitive function in children with Down syndrome. Its efficacy, however, has not been rigorously assessed. OBJECTIVE: To determine whether 4 months of piracetam therapy (80-100 mg/kg per day) enhances cognitive function in children with Down syndrome. DESIGN: A randomized, double-blind, placebo-controlled crossover study. PARTICIPANTS AND METHODS: Twenty-five children with Down syndrome (aged 6.5-13 years) and their caregivers participated. After undergoing a baseline cognitive assessment, children were randomly assigned to 1 of 2 treatment groups: piracetam-placebo or placebo-piracetam. MAIN OUTCOME MEASURE: The difference in performance while taking piracetam vs while taking placebo on tests assessing a wide range of cognitive functions, including attention, learning, and memory. RESULTS: Eighteen children completed the study, 4 withdrew, and 3 were excluded at baseline. Piracetam therapy did not significantly improve cognitive performance over placebo use but was associated with central nervous system stimulatory effects in 7 children: aggressiveness (n = 4), agitation or irritability (n = 2), sexual arousal (n = 2), poor sleep (n = 1), and decreased appetite (n = 1). CONCLUSION: Piracetam therapy did not enhance cognition or behavior but was associated with adverse effects.

Learning and memory in S100-beta transgenic mice: an analysis of impaired and preserved function.

S100-beta, a calcium-binding astrocytic protein from chromosome 21, has been implicated in CNS function generally and the hippocampus in particular. Elevated levels of S100-beta have been observed reliably in the brains of patients with Alzheimer's Disease and Down Syndrome. Groups of transgenic mice, carrying multiple S100-beta gene copies, and nontransgenic controls were administered a series of behavioral tests (delayed spatial and nonspatial non-matching-to-sample, radial arm maze, socially acquired food preference) that assessed a wide range of cognitive functions. Consistent with the widespread presence of S100-beta throughout the brain, transgenic mice exhibited learning or memory impairment on all tasks. The dementia-like cognitive profile of S100-beta mice represents a promising model for studying comparable cognitive deficits associated with neurodegenerative diseases.

Three brain SPECT region-of-interest templates in elderly people: normative values, hemispheric asymmetries, and a comparison of single- and multihead cameras.

UNLABELLED: The purpose of this study was to generate anatomically guided region-of-interest (ROI) brain SPECT templates based on scans of elderly healthy volunteers. We describe normal tracer uptake and hemispheric asymmetries for each of 3 camera systems and compare these characteristics among systems. METHODS: 99mTc-hexamethyl propyleneamine oxime SPECT scans were acquired from 28 elderly healthy volunteers (mean age [+/-SD], 70.3 +/- 6.5 y) on a single-head rotating gamma camera (n = 15) or on dual- (n = 18) or triple-head (n = 13) cameras. The average number of counts in each ROI was calculated and referenced to counts in a cerebellar ROI, providing semiquantitative regional cerebral blood flow (rCBF) ratios. For the templates and ROI map, base images of a healthy volunteer were obtained with each camera. Data from individuals scanned with 2 cameras on the same day (n = 15) were used to evaluate rCBF differences across cameras. For each camera, averaged SPECT templates were made using automated image registration. The base volunteer's T1-weighted MR image was converted to stereotactic space with dimensions similar to those of the SPECT templates, and 79 bilateral ROIs were defined. To obtain ROI rCBF ratios, we aligned individual images to their appropriate template and then to this modified MR image. RESULTS: The ROI coefficients of variation indicated that the fit of the ROIs was acceptable (0.07-0.35). Mean rCBF ratios ranged from 0.57 to 1.0, 0.67 to 1.01, and 0.63 to 1.00 for single-, dual-, and triple-head cameras, respectively. The cuneus, occipital cortex, occipital pole, middle temporal gyrus, and posterior middle frontal gyrus showed consistent hemispheric asymmetry (right side greater than left side in 83%-100% of individuals). Mean rCBF ratios did not differ between dual- and triple-head cameras, whereas the ratios for single- and dual-head cameras differed significantly (39 ROIs differed), even after smoothing and filtering the dual-head images to the level of the single-head images. CONCLUSION: The use of SPECT templates based on elderly healthy volunteers is an important feature of this technique because most available templates have used young individuals. Another important feature is the use of MR image-based ROIs. These procedures are versatile because they use more than 1 camera. They can easily be implemented in clinical and research settings to detect camera-specific, abnormal deviations in rCBF ROI ratios and asymmetry magnitudes in diseases associated with aging, such as stroke and dementia.

Interactions of prefrontal cortex in relation to awareness in sensory learning.

In an associative learning paradigm, human subjects could be divided based on whether they were aware that one tone predicted a visual event and another did not. Only aware subjects acquired a differential behavioral response to the tones. Regional cerebral blood flow in left prefrontal cortex showed learning-related changes only in aware subjects. Left prefrontal cortex also showed changes in functional connectivity with contralateral prefrontal cortex, sensory association cortices, and cerebellum. Several of the interacting areas correlated with aware subjects' behavior. These results suggest cerebral processes underlying awareness are mediated through interactions of large-scale neurocognitive systems.

Analysis of neural interactions explains the activation of occipital cortex by an auditory stimulus.

Analysis of neural interactions explains the activation of occipital cortex by an auditory stimulus. J. Neurophysiol. 80: 2790-2796, 1998. Large-scale neural interactions were characterized in human subjects as they learned that an auditory stimulus signaled a visual event. Once learned, activation of left dorsal occipital cortex (increased regional cerebral blood flow) was observed when the auditory stimulus was presented alone. Partial least-squares analysis of the interregional correlations (functional connectivity) between the occipital area and the rest of the brain identified a pattern of covariation with four dominant brain areas that could have mediated this activation: prefrontal cortex (near Brodmann area 10, A10), premotor cortex (A6), superior temporal cortex (A41/42), and contralateral occipital cortex (A18). Interactions among these regions and the occipital area were quantified with structural equation modeling to identify the strongest sources of the effect on left occipital activity (effective connectivity). Learning-related changes in feedback effects from A10 and A41/42 appeared to account for this change in occipital activity. Influences from these areas on the occipital area were initially suppressive, or negative, becoming facilitory, or positive, as the association between the auditory and visual stimuli was acquired. Evaluating the total effects within the functional models showed positive influences throughout the network, suggesting enhanced interactions may have primed the system for the now-expected visual discrimination. By characterizing both changes in activity and the interactions underlying sensory associative learning, we demonstrated how parts of the nervous system operate as a cohesive network in learning about and responding to the environment.

Convergence of neural systems processing stimulus associations and coordinating motor responses.

A sensory-sensory learning paradigm was used to measure neural changes in humans during acquisition of an association between an auditory and visual stimulus. Three multivariate partial least-squares (PLS) analyses of positron emission tomography data identified distributed neural systems related to (i) processing the significance of the auditory stimulus, (ii) mediating the acquisition of the behavioral response, and (iii) the spatial overlap between these two systems. The system that processed the significance of the tone engaged primarily right hemisphere regions and included dorsolateral prefrontal cortex, putamen, and inferior parietal and temporal cortices. Activity changes in left occipital cortex were also identified, most likely reflecting the learned expectancy of the upcoming visual event. The system related to behavior was similar to that which coded the significance of the tone, including dorsal occipital cortex. The PLS analysis of the concordance between these two systems showed substantial regional overlap, and included occipital, dorsolateral prefrontal, and limbic cortices. However, activity in dorsomedial prefrontal cortex was strictly related to processing the auditory stimulus and not to behavior. Taken together, the PLS analyses identified a system that contained a sensory-motor component (comprised of occipital, temporal association and sensorimotor cortices) and a medial prefrontallimbic component, that as a group simultaneously embodied the learning-related response to the stimuli and the subsequent change in behavior.