EEG-fMRI Signal Coupling Is Modulated in Subjects With Mild Cognitive Impairment and Amyloid Deposition.

Cognitive impairment indicates disturbed brain physiology which can be due to various mechanisms including Alzheimer's pathology. Combined functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) recordings (EEG-fMRI) can assess the interplay between complementary measures of brain activity and EEG changes to be localized to specific brain regions. We used a two-step approach, where we first examined changes related to a syndrome of mild cognitive impairment irrespective of pathology and then studied the specific impact of amyloid pathology. After detailed clinical and neuropsychological characterization as well as a positron emission tomography (PET) scans with the tracer 11-[C]-Pittsburgh Compound B to estimate cerebral amyloid deposition, 14 subjects with mild cognitive impairment (MCI) (mean age 75.6 SD: 8.9) according to standard criteria and 21 cognitively healthy controls (HCS) (mean age 71.8 SD: 4.2) were assessed with EEG-fMRI. Thalamo-cortical alpha-fMRI signal coupling was only observed in HCS. Additional EEG-fMRI signal coupling differences between HCS and MCI were observed in parts of the default mode network, salience network, fronto-parietal network, and thalamus. Individuals with significant cerebral amyloid deposition (amyloid-positive MCI and HCS combined compared to amyloid-negative HCS) displayed abnormal EEG-fMRI signal coupling in visual, fronto-parietal regions but also in the parahippocampus, brain stem, and cerebellum. This finding was paralleled by stronger absolute fMRI signal in the parahippocampus and weaker absolute fMRI signal in the inferior frontal gyrus in amyloid-positive subjects. We conclude that the thalamocortical coupling in the alpha band in HCS more closely reflects previous findings observed in younger adults, while in MCI there is a clearly aberrant coupling in several networks dominated by an anticorrelation in the posterior cingulate cortex. While these findings may broadly indicate physiological changes in MCI, amyloid pathology was specifically associated with abnormal fMRI signal responses and disrupted coupling between brain oscillations and fMRI signal responses, which especially involve core regions of memory: the hippocampus, para-hippocampus, and lateral prefrontal cortex.

Increased cerebral blood volume in small arterial vessels is a correlate of amyloid-ß-related cognitive decline.

The protracted accumulation of amyloid-ß (Aß) is a major pathologic hallmark of Alzheimer's disease and may trigger secondary pathological processes that include neurovascular damage. This study was aimed at investigating long-term effects of Aß burden on cerebral blood volume of arterioles and pial arteries (CBVa), possibly present before manifestation of dementia. Aß burden was assessed by 11C Pittsburgh compound-B positron emission tomography in 22 controls and 18 persons with mild cognitive impairment (MCI), [ages: 75(±6) years]. After 2 years, inflow-based vascular space occupancy at ultra-high field strength of 7-Tesla was administered for measuring CBVa, and neuropsychological testing for cognitive decline. Crushing gradients were incorporated during MR-imaging to suppress signals from fast-flowing blood in large arteries, and thereby sensitize inflow-based vascular space occupancy to CBVa in pial arteries and arterioles. CBVa was significantly elevated in MCI compared to cognitively normal controls and regional CBVa related to local Aß deposition. For both MCI and controls, Aß burden and follow-up CBVa in several brain regions synergistically predicted cognitive decline over 2 years. Orbitofrontal CBVa was positively associated with apolipoprotein E e4 carrier status. Increased CBVa may reflect long-term effects of region-specific pathology associated with Aß deposition. Additional studies are needed to clarify the role of the arteriolar system and the potential of CBVa as a biomarker for Aß-related vascular downstream pathology.

Low cortical iron and high entorhinal cortex volume promote cognitive functioning in the oldest-old.

The aging brain is characterized by an increased presence of neurodegenerative and vascular pathologies. However, there is substantial variation regarding the relationship between an individual's pathological burden and resulting cognitive impairment. To identify correlates of preserved cognitive functioning at highest age, the relationship between ß-amyloid plaque load, presence of small vessel cerebrovascular disease (SVCD), iron-burden, and brain atrophy was investigated. Eighty cognitively unimpaired participants (44 oldest-old, aged 85-96 years; 36 younger-old, aged 55-80 years) were scanned by integrated positron emission tomography-magnetic resonance imaging for assessing beta regional amyloid plaque load (18F-flutemetamol), white matter hyperintensities as an indicator of SVCD (fluid-attenuated inversion recovery-magnetic resonance imaging), and iron load (quantitative susceptibility mapping). For the oldest-old group, lower cortical volume, increased ß-amyloid plaque load, prevalence of SVCD, and lower cognitive performance in the normal range were found. However, compared to normal-old, cortical iron burden was lower in the oldest-old. Moreover, only in the oldest-old, entorhinal cortex volume positively correlated with ß-amyloid plaque load. Our data thus indicate that the co-occurrence of aging-associated neuropathologies with reduced quantitative susceptibility mapping measures of cortical iron load constitutes a lower vulnerability to cognitive loss.

Brain amyloid burden and cerebrovascular disease are synergistically associated with neurometabolism in cognitively unimpaired older adults.

Alzheimer's disease (AD) is the most common cause of cognitive dysfunction in older adults. The pathological hallmarks of AD such as beta amyloid (Aß) aggregation and neurometabolic change, as indicated by altered myo-inositol (mI) and N-acetylaspartate (NAA) levels, typically precede the onset of cognitive dysfunction by years. Furthermore, cerebrovascular disease occurs early in AD, but the interplay between vascular and neurometabolic brain change is largely unknown. Thirty cognitively normal older adults (age = 70 ± 5.6 years, Mini-Mental State Examination = 29.2 ± 1) received 11-C-Pittsburgh Compound B positron emission tomography for estimating Aß-plaque density, 7 Tesla fluid-attenuated inversion recovery magnetic resonance imaging for quantifying white matter hyperintensity volume as a marker of small vessel cerebrovascular disease and high-resolution magnetic resonance spectroscopic imaging at 7 Tesla, based on free induction decay acquisition localized by outer volume suppression to investigate tissue-specific neurometabolism in the posterior cingulate and precuneus. Aß (ß = 0.45, p = 0.018) and white matter hyperintensities (ß = 0.40, p = 0.046) were independently and interactively (ß = -0.49, p = 0.026) associated with a higher ratio of mI over NAA (mI/NAA) in the posterior cingulate and precuneus gray matter but not in the white matter. Our data suggest that cerebrovascular disease and Aß burden are synergistically associated with AD-related gray matter neurometabolism in older adults.

Changes of Functional and Directed Resting-State Connectivity Are Associated with Neuronal Oscillations, ApoE Genotype and Amyloid Deposition in Mild Cognitive Impairment.

The assessment of effects associated with cognitive impairment using electroencephalography (EEG) power mapping allows the visualization of frequency-band specific local changes in oscillatory activity. In contrast, measures of coherence and dynamic source synchronization allow for the study of functional and effective connectivity, respectively. Yet, these measures have rarely been assessed in parallel in the context of mild cognitive impairment (MCI) and furthermore it has not been examined if they are related to risk factors of Alzheimer's disease (AD) such as amyloid deposition and apolipoprotein ε4 (ApoE) allele occurrence. Here, we investigated functional and directed connectivities with Renormalized Partial Directed Coherence (RPDC) in 17 healthy controls (HC) and 17 participants with MCI. Participants underwent ApoE-genotyping and Pittsburgh compound B positron emission tomography (PiB-PET) to assess amyloid deposition. We observed lower spectral source power in MCI in the alpha and beta bands. Coherence was stronger in HC than MCI across different neuronal sources in the delta, theta, alpha, beta and gamma bands. The directed coherence analysis indicated lower information flow between fronto-temporal (including the hippocampus) sources and unidirectional connectivity in MCI. In MCI, alpha and beta RPDC showed an inverse correlation to age and gender; global amyloid deposition was inversely correlated to alpha coherence, RPDC and beta and gamma coherence. Furthermore, the ApoE status was negatively correlated to alpha coherence and RPDC, beta RPDC and gamma coherence. A classification analysis of cognitive state revealed the highest accuracy using EEG power, coherence and RPDC as input. For this small but statistically robust (Bayesian power analyses) sample, our results suggest that resting EEG related functional and directed connectivities are sensitive to the cognitive state and are linked to ApoE and amyloid burden.

Memory performance-related dynamic brain connectivity indicates pathological burden and genetic risk for Alzheimer's disease.

BACKGROUND: The incidence of Alzheimer's disease (AD) strongly relates to advanced age and progressive deposition of cerebral amyloid-beta (Aß), hyperphosphorylated tau, and iron. The purpose of this study was to investigate the relationship between cerebral dynamic functional connectivity and variability of long-term cognitive performance in healthy, elderly subjects, allowing for local pathology and genetic risk. METHODS: Thirty seven participants (mean (SD) age 74 (6.0) years, Mini-Mental State Examination 29.0 (1.2)) were dichotomized based on repeated neuropsychological test performance within 2 years. Cerebral Aß was measured by 11C Pittsburgh Compound-B positron emission tomography, and iron by quantitative susceptibility mapping magnetic resonance imaging (MRI) at an ultra-high field strength of 7 Tesla (7T). Dynamic functional connectivity patterns were investigated by resting-state functional MRI at 7T and tested for interactive effects with genetic AD risk (apolipoprotein E (ApoE)-ε4 carrier status). RESULTS: A relationship between low episodic memory and a lower expression of anterior-posterior connectivity was seen (F(9,27) = 3.23, p < 0.008), moderated by ApoE-ε4 (F(9,27) = 2.22, p < 0.005). Inherent node-strength was related to local iron (F(5,30) = 13.2; p < 0.022). CONCLUSION: Our data indicate that altered dynamic anterior-posterior brain connectivity is a characteristic of low memory performance in the subclinical range and genetic risk for AD in the elderly. As the observed altered brain network properties are associated with increased local iron, our findings may reflect secondary neuronal changes due to pathologic processes including oxidative stress.

Subcortical Shape Changes, Hippocampal Atrophy and Cortical Thinning in Future Alzheimer's Disease Patients.

Efficacy of future treatments depends on biomarkers identifying patients with mild cognitive impairment at highest risk for transitioning to Alzheimer's disease. Here, we applied recently developed analysis techniques to investigate cross-sectional differences in subcortical shape and volume alterations in patients with stable mild cognitive impairment (MCI) (n = 23, age range 59-82, 47.8% female), future converters at baseline (n = 10, age range 66-84, 90% female) and at time of conversion (age range 68-87) compared to group-wise age and gender matched healthy control subjects (n = 23, age range 61-81, 47.8% female; n = 10, age range 66-82, 80% female; n = 10, age range 68-82, 70% female). Additionally, we studied cortical thinning and global and local measures of hippocampal atrophy as known key imaging markers for Alzheimer's disease. Apart from bilateral striatal volume reductions, no morphometric alterations were found in cognitively stable patients. In contrast, we identified shape alterations in striatal and thalamic regions in future converters at baseline and at time of conversion. These shape alterations were paralleled by Alzheimer's disease like patterns of left hemispheric morphometric changes (cortical thinning in medial temporal regions, hippocampal total and subfield atrophy) in future converters at baseline with progression to similar right hemispheric alterations at time of conversion. Additionally, receiver operating characteristic curve analysis indicated that subcortical shape alterations may outperform hippocampal volume in identifying future converters at baseline. These results further confirm the key role of early cortical thinning and hippocampal atrophy in the early detection of Alzheimer's disease. But first and foremost, and by distinguishing future converters but not patients with stable cognitive abilities from cognitively normal subjects, our results support the value of early subcortical shape alterations and reduced hippocampal subfield volumes as potential markers for the early detection of Alzheimer's disease.

Hippocampal shape alterations are associated with regional Aß load in cognitively normal elderly individuals.

Aß deposition is a driving force of Alzheimer's disease pathology and can be detected early by amyloid positron emission tomography. Identifying presymptomatic structural brain changes associated with Aß deposition might lead to a better understanding of its consequences and provide early diagnostic information. In this respect we analyzed measures of cortical thickness and subcortical volumes along with hippocampal, thalamic and striatal shape and surface area by applying novel analysis strategies for structural magnetic resonance imaging. We included 69 cognitively normal elderly subjects after careful clinical and neuropsychological workup. Standardized uptake value ratios (cerebellar reference) for uptake of 11-C-Pittsburgh Compound B (PiB) were calculated from positron emission tomographic data for a cortical measurement and for bilateral hippocampus, thalamus and striatum. Associations to shape, surface area, volume and cortical thickness were tested using regression models that included significant predictors as covariates. Left anterior hippocampal shape was associated with regional PiB uptake (P < 0.05, FDR corrected), whereas volumes of the hippocampi and their subregions were not associated with cortical or regional PiB uptake (all P > 0.05, FDR corrected). Within the entorhinal cortical region of both hemispheres, thickness was negatively associated with cortical PiB uptake (P < 0.05, FDR corrected). Hence, localized shape measures and cortical thickness may be potential biomarkers of presymptomatic Alzheimer's disease.

Microstructural Integrity of Hippocampal Subregions Is Impaired after Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) affects a large number of individuals and diffusion tensor imaging can be used to investigate microstructural integrity of brain tissue after mTBI. However, results have varied considerably between studies and gray matter (GM) integrity has been largely neglected in these investigations. Given impaired working memory processing after mTBI and its possible association with Alzheimer's disease, we investigated hippocampal integrity and parcellated this structure into five subregions: subiculum, cornu ammonis (CA) 1, CA 2/3, CA 4/dentate gyrus, and stratum radiatum/lacunosum-moleculare. We also employed shape analysis of bilateral hippocampi to explore whether morphological changes had occurred due to the traumatic injury and conducted neuropsychological memory tests. The sample comprised 15 subjects with mTBI (18-55 years, nine female) and 13 age- and sex-matched healthy control subjects (19-57 years, nine female). Voxelwise analyses showed significantly increased mean diffusivity in patients, compared with controls, in the right hippocampus and three of its five subregions (family-wise error corrected p < 0.05). Additionally, results from probabilistic tractography indicated impaired CA 1 connectivity after mTBI (Benjamini-Hochberg false discovery rate [FDR] corrected p < 0.05). Shape of bilateral hippocampi did not significantly differ between groups (Benjamini-Hochberg FDR corrected p > 0.05). Subjects with mTBI reported more symptoms and performed worse in a non-standard verbal working memory task. Based on these preliminary findings, we were able to demonstrate altered diffusivity of hippocampal subregions following mTBI, indicating impaired GM microstructural integrity. These differences highlight the potential of diffusion imaging for investigation of subtle yet relevant changes in GM microstructure not detected otherwise following mTBI.

Low episodic memory performance in cognitively normal elderly subjects is associated with increased posterior cingulate gray matter N-acetylaspartate: a 1H MRSI study at 7 Tesla.

Low episodic memory performance characterizes elderly subjects at increased risk for Alzheimer's disease (AD) and may reflect neuronal dysfunction within the posterior cingulate cortex and precuneus (PCP) region. To investigate a potential association between cerebral neurometabolism and low episodic memory in the absence of cognitive impairment, tissue-specific magnetic resonance spectroscopic imaging at ultrahigh field strength of 7 Tesla was used to investigate the PCP region in a healthy elderly study population (n = 30, age 70 ± 5.7 years, Mini-Mental State Examination 29.4 ± 4.1). The Verbal Learning and Memory Test (VLMT) was administered as part of a neuropsychological battery for assessment of episodic memory performance. Significant differences between PCP gray and white matter could be observed for glutamate-glutamine (p = 0.001), choline (p = 0.01), and myo-inositol (p = 0.02). Low Verbal Learning and Memory Test performance was associated with high N-acetylaspartate in PCP gray matter (p = 0.01) but not in PCP white matter. Our data suggest that subtle decreases in episodic memory performance in the elderly may be associated with increased levels of N-acetylaspartate as a reflection of increased mitochondrial energy capacity in PCP gray matter.

Volumetric and shape analysis of the thalamus and striatum in amnestic mild cognitive impairment.

Alterations in brain structures, including progressive neurodegeneration, are a hallmark in patients with Alzheimer's disease (AD). However, pathological mechanisms, such as the accumulation of amyloid and the proliferation of tau, are thought to begin years, even decades, before the initial clinical manifestations of AD. In this study, we compare the brain anatomy of amnestic mild cognitive impairment patients (aMCI, n = 16) to healthy subjects (CS, n = 22) using cortical thickness, subcortical volume, and shape analysis, which we believe to be complimentary to volumetric measures. We were able to replicate "classical" cortical thickness alterations in aMCI in the hippocampus, amygdala, putamen, insula, and inferior temporal regions. Additionally, aMCI showed significant thalamic and striatal shape differences. We observed higher global amyloid deposition in aMCI, a significant correlation between striatal displacement and global amyloid, and an inverse correlation between executive function and right-hemispheric thalamic displacement. In contrast, no volumetric differences were detected in thalamic, striatal, and hippocampal regions. Our results provide new evidence for early subcortical neuroanatomical changes in patients with aMCI, which are linked to cognitive abilities and amyloid deposition. Hence, shape analysis may aid in the identification of structural biomarkers for identifying individuals at highest risk of conversion to AD.

Arterial spin labeling imaging reveals widespread and Aß-independent reductions in cerebral blood flow in elderly apolipoprotein epsilon-4 carriers.

Changes in cerebral blood flow are an essential feature of Alzheimer's disease and have been linked to apolipoprotein E-genotype and cerebral amyloid-deposition. These factors could be interdependent or influence cerebral blood flow via different mechanisms. We examined apolipoprotein E-genotype, amyloid beta-deposition, and cerebral blood flow in amnestic mild cognitive impairment using pseudo-continuous arterial spin labeling MRI in 27 cognitively normal elderly and 16 amnestic mild cognitive impairment participants. Subjects underwent Pittsburgh Compound B (PiB) positron emission tomography and apolipoprotein E-genotyping. Global cerebral blood flow was lower in apolipoprotein E ɛ4-allele carriers (apolipoprotein E4+) than in apolipoprotein E4- across all subjects (including cognitively normal participants) and within the group of cognitively normal elderly. Global cerebral blood flow was lower in subjects with mild cognitive impairment compared with cognitively normal. Subjects with elevated cerebral amyloid-deposition (PiB+) showed a trend for lower global cerebral blood flow. Apolipoprotein E-status exerted the strongest effect on global cerebral blood flow. Regional analysis indicated that local cerebral blood flow reductions were more widespread for the contrasts apolipoprotein E4+ versus apolipoprotein E4- compared with the contrasts PiB+ versus PiB- or mild cognitive impairment versus cognitively normal. These findings suggest that apolipoprotein E-genotype exerts its impact on cerebral blood flow at least partly independently from amyloid beta-deposition, suggesting that apolipoprotein E also contributes to cerebral blood flow changes outside the context of Alzheimer's disease.

Regional cerebral blood flow estimated by early PiB uptake is reduced in mild cognitive impairment and associated with age in an amyloid-dependent manner.

Early uptake of [(11)C]-Pittsburgh Compound B (ePiB, 0-6 minutes) estimates cerebral blood flow. We studied ePiB in 13 PiB-negative and 10 PiB-positive subjects with mild cognitive impairment (MCI, n = 23) and 11 PiB-positive and 74 PiB-negative cognitively healthy elderly control subjects (HCS, n = 85) in 6 bilateral volumes of interest: posterior cingulate cortex (PCC), hippocampus (hipp), temporoparietal region, superior parietal gyrus, parahippocampal gyrus (parahipp), and inferior frontal gyrus (IFG) for the associations with cognitive status, age, amyloid deposition, and apolipoprotein E ε4-allele. We observed no difference in ePiB between PiB-positive and -negative subjects and carriers and noncarriers. EPiB decreased with age in PiB-positive subjects in bilateral superior parietal gyrus, bilateral temporoparietal region, right IFG, right PCC, and left parahippocampal gyrus but not in PiB-negative subjects. MCI had lower ePiB than HCS (left PCC, left IFG, and left and right hipp). Lowest ePiB values were found in MCI of 70 years and older, who also displayed high cortical PiB binding. This suggests that lowered regional cerebral blood flow indicated by ePiB is associated with age in the presence but not in the absence of amyloid pathology.

Posterior cingulate γ-aminobutyric acid and glutamate/glutamine are reduced in amnestic mild cognitive impairment and are unrelated to amyloid deposition and apolipoprotein E genotype.

The biomarker potential of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) for the in vivo characterization of preclinical stages in Alzheimer's disease has not yet been explored. We measured GABA, glutamate + glutamine (Glx), and N-acetyl-aspartate (NAA) levels by single-voxel MEGA-PRESS magnetic resonance spectroscopy in the posterior cingulate cortex of 21 elderly subjects and 15 patients with amnestic mild cognitive impairment. Participants underwent Pittsburgh Compound B positron emission tomography, apolipoprotein E (APOE) genotyping, and neuropsychological examination. GABA, Glx, and NAA levels were significantly lower in patients. NAA was lower in Pittsburgh Compound B-positive subjects and APOE ε4 allele carriers. GABA, Glx, and NAA levels were positively correlated to CERAD word learning scores. Reductions in GABA, Glx, and NAA levels may serve as metabolic biomarkers for cognitive impairment in amnestic mild cognitive impairment. Because GABA and Glx do not seem to reflect amyloid ß deposition or APOE genotype, they are less likely biomarker candidates for preclinical Alzheimer's disease.

Regional Fluid-Attenuated Inversion Recovery (FLAIR) at 7 Tesla correlates with amyloid beta in hippocampus and brainstem of cognitively normal elderly subjects.

BACKGROUND: Accumulation of amyloid beta (Aß) may occur during healthy aging and is a risk factor for Alzheimer Disease (AD). While individual Aß-accumulation can be measured non-invasively using Pittsburgh Compund-B positron emission tomography (PiB-PET), Fluid-attenuated inversion recovery (FLAIR) is a Magnetic Resonance Imaging (MRI) sequence, capable of indicating heterogeneous age-related brain pathologies associated with tissue-edema. In the current study cognitively normal elderly subjects were investigated for regional correlation of PiB- and FLAIR intensity. METHODS: Fourteen healthy elderly subjects without known history of cognitive impairment received 11C-PiB-PET for estimation of regional Aß-load. In addition, whole brain T1-MPRAGE and FLAIR-MRI sequences were acquired at high field strength of 7 Tesla (7T). Volume-normalized intensities of brain regions were assessed by applying an automated subcortical segmentation algorithm for spatial definition of brain structures. Statistical dependence between FLAIR- and PiB-PET intensities was tested using Spearman's rank correlation coefficient (rho), followed by Holm-Bonferroni correction for multiple testing. RESULTS: Neuropsychological testing revealed normal cognitive performance levels in all participants. Mean regional PiB-PET and FLAIR intensities were normally distributed and independent. Significant correlation between volume-normalized PiB-PET signals and FLAIR intensities resulted for Hippocampus (right: rho = 0.86; left: rho = 0.84), Brainstem (rho = 0.85) and left Basal Ganglia vessel region (rho = 0.82). CONCLUSIONS: Our finding of a significant relationship between PiB- and FLAIR intensity mainly observable in the Hippocampus and Brainstem, indicates regional Aß associated tissue-edema in cognitively normal elderly subjects. Further studies including clinical populations are necessary to clarify the relevance of our findings for estimating individual risk for age-related neurodegenerative processes such as AD.

Superior colliculi involvement in poststroke unilateral spatial neglect: a pilot study.

PURPOSE: The neural mechanisms underlying unilateral spatial neglect (USN) are unclear. The superior colliculi (SC) may be involved in USN expression, and the spatial summation effect (SSE), where reaction times to bilateral stimuli are faster than to unilateral, may be a behavioral index of SC function. We determined the feasibility of investigating SC contribution to poststroke USN using the SSE in 3 groups. METHODS: Seven participants with left near-extrapersonal space USN (USN+) following right hemisphere stroke, 10 without (USN-), and 10 controls were tested under binocular/monocular (right eye patched) conditions while responding to unilateral/bilateral stimuli. Control and USN- groups completed the SSE paradigm. RESULTS: Most USN+ participants were unable to initiate the SSE paradigm due to poor visual fi xation and demonstrated higher contrast sensitivity for left-sided stimuli. Controls showed an SSE (under both viewing conditions) while the USN- showed an abnormal SSE whereby reaction times to bilateral stimuli were faster than to unilateral-left but not to unilateral-right stimuli (under both binocular/monocular conditions). CONCLUSION: This study is the fi rst to investigate SC contribution in poststroke USN using the SSE; we identifi ed higher contrast sensitivity to left-sided stimuli and poor fi xation in the USN+ group. These fi ndings suggest avenues for research that may lead to novel rehabilitation interventions.

The neural circuitry of executive functions in healthy subjects and Parkinson's disease.

In our constantly changing environment, we are frequently faced with altered circumstances requiring generation and monitoring of appropriate strategies, when novel plans of action must be formulated and conducted. The abilities that we call upon to respond accurately to novel situations are referred to as 'executive functions', and are frequently engaged to deal with conditions in which routine activation of behavior would not be sufficient for optimal performance. Here, we summarize important findings that may help us understand executive functions and their underlying neuronal correlates. We focus particularly on observations from imaging technology, such as functional magnetic resonance imaging, position emission tomography, diffusion tensor imaging, and transcranial magnetic stimulation, which in the past few years have provided the bulk of information on the neurobiological underpinnings of the executive functions. Further, emphasis will be placed on recent insights from Parkinson's disease (PD), in which the underlying dopaminergic abnormalities have provided new exciting information into basic molecular mechanisms of executive dysfunction, and which may help to disentangle the cortical/subcortical networks involved in executive processes.

Blindsight mediated by an S-cone-independent collicular pathway: an fMRI study in hemispherectomized subjects.

The purpose of our study was to investigate the ability to process achromatic and short-wavelength-sensitive cone (S-cone)-isolating (blue-yellow) stimuli in the blind visual field of hemispherectomized subjects and to demonstrate that blindsight is mediated by a collicular pathway that is independent of S-cone inputs. Blindsight has been described as the ability to respond to visual stimuli in the blind visual field without conscious awareness [Weiskrantz, L., Warrington, E. K., Sanders, M. D., & Marshall, J. Visual capacity in the hemianopic field following a restricted occipital ablation. Brain, 97, 709-728, 1974]. The roles of the subcortical neural structures in blindsight, such as the pulvinar and the superior colliculus, have been debated and an underlying neural correlate has yet to be confirmed. Using fMRI, we tested the ability to process visual stimuli that isolated the achromatic and short-wavelength-sensitive (S-)-cone pathways in three subjects: one control subject, one hemispherectomized subject with blindsight, and one hemispherectomized subject without blindsight. We demonstrated that (1) achromatic and S-cone-isolating stimuli presented to the normal visual hemifield of hemispherectomized subjects and to both visual hemifields of the control subject activated contralateral visual areas (V1/V2), as expected; (2) achromatic stimulus presentation but not S-cone-isolating stimulus presentation to the blind hemifield of the subject with blindsight activated visual areas FEF/V5; (3) whereas the cortical activation of the control subject was enhanced by an additional stimulus (achromatic and S-cone isolating) presented in the contralateral visual field, activation pattern of the subject with blindsight was enhanced by achromatic stimuli only. We conclude that the human superior colliculus is blind to the S-cone-isolating stimuli, and blindsight is mediated by an S-cone-independent collicular pathway.

Right impairment of temporal order judgements in dyslexic children.

This study investigates the spatial bias of visual attention measured by a temporal order judgement (TOJ) task and the influence of a high attentional load condition in a group of dyslexic children compared to a control group with normal reading skills (each group N=10). The TOJ task (T2) was placed after a shape discrimination task (T1). In a low attentional load block participants worked only on T2, whereas in the high attentional load block they were required to process both T1 and T2. Several t-tests were executed to compare performance between conditions and groups. In the low attentional load conditions, results in dyslexic children were significantly impaired for the right visual field compared to a control group. The high attentional load conditions did not enhance these effects and seems to provoke the same leftward bias in the control group.

The connectivity of the human pulvinar: a diffusion tensor imaging tractography study.

Previous studies in nonhuman primates and cats have shown that the pulvinar receives input from various cortical and subcortical areas involved in vision. Although the contribution of the pulvinar to human vision remains to be established, anatomical tracer and electrophysiological animal studies on cortico-pulvinar circuits suggest an important role of this structure in visual spatial attention, visual integration, and higher-order visual processing. Because methodological constraints limit investigations of the human pulvinar's function, its role could, up to now, only be inferred from animal studies. In the present study, we used an innovative imaging technique, Diffusion Tensor Imaging (DTI) tractography, to determine cortical and subcortical connections of the human pulvinar. We were able to reconstruct pulvinar fiber tracts and compare variability across subjects in vivo. Here we demonstrate that the human pulvinar is interconnected with subcortical structures (superior colliculus, thalamus, and caudate nucleus) as well as with cortical regions (primary visual areas (area 17), secondary visual areas (area 18, 19), visual inferotemporal areas (area 20), posterior parietal association areas (area 7), frontal eye fields and prefrontal areas). These results are consistent with the connectivity reported in animal anatomical studies.