Locus coeruleus integrity in old age is selectively related to memories linked with salient negative events.

The locus coeruleus (LC) is the principal origin of noradrenaline in the brain. LC integrity varies considerably across healthy older individuals, and is suggested to contribute to altered cognitive functions in aging. Here we test this hypothesis using an incidental memory task that is known to be susceptible to noradrenergic modulation. We used MRI neuromelanin (NM) imaging to assess LC structural integrity and pupillometry as a putative index of LC activation in both younger and older adults. We show that older adults with reduced structural LC integrity show poorer subsequent memory. This effect is more pronounced for emotionally negative events, in accord with a greater role for noradrenergic modulation in encoding salient or aversive events. In addition, we found that salient stimuli led to greater pupil diameters, consistent with increased LC activation during the encoding of such events. Our study presents novel evidence that a decrement in noradrenergic modulation impacts on specific components of cognition in healthy older adults. The findings provide a strong motivation for further investigation of the effects of altered LC integrity in pathological aging.

Foveal pRF properties in the visual cortex depend on the extent of stimulated visual field.

Previous studies demonstrated that alterations in functional MRI derived receptive field (pRF) properties in cortical projection zones of retinal lesions can erroneously be mistaken for cortical large-scale reorganization in response to visual system pathologies. We tested, whether such confounds are also evident in the normal cortical projection zone of the fovea for simulated peripheral visual field defects. We applied fMRI-based visual field mapping of the central visual field at 3 T in eight controls to compare the pRF properties of the central visual field of a reference condition (stimulus radius: 14°) and two conditions with simulated peripheral visual field defect, i.e., with a peripheral gray mask, stimulating only the central 7° or 4° radius. We quantified, for the cortical representation of the actually stimulated visual field, the changes in the position and size of the pRFs associated with reduced peripheral stimulation using conventional and advanced pRF modeling. We found foveal pRF-positions (≤3°) to be significantly shifted towards the periphery (p<0.05, corrected). These pRF-shifts were largest for the 4° condition [visual area (mean eccentricity shift): V1 (0.9°), V2 (0.9°), V3 (1.0°)], but also evident for the 7° condition [V1 (0.5°), V2 (0.5°), V3 (0.9°)]. Further, an overall enlargement of pRF-sizes was observed. These findings indicate the dependence of foveal pRF parameters on the spatial extent of the stimulated visual field and are likely associated with methodological biases and/or physiological mechanisms. Consequently, our results imply that, previously reported similar findings in patients with actual peripheral scotomas need to be interpreted with caution and indicate the need for adequate control conditions in investigations of visual cortex reorganization.

Orbitofrontal Signaling of Future Reward is Associated with Hyperactivity in Attention-Deficit/Hyperactivity Disorder.

Alterations in motivated behavior are a hallmark of attention-deficit/hyperactivity disorder (ADHD), one of the most common psychiatric disorders in children and adolescents. The orbitofrontal cortex (OFC) plays a key role in controlling goal-directed behavior, but the link between OFC dysfunction and behavioral deficits in ADHD, particularly in adolescence, remains poorly understood. Here we used advanced high-resolution functional magnetic resonance imaging (fMRI) of the human OFC in adolescents with ADHD and typically developing (TD) controls (N = 39, age 12-16, all male except for one female per group) to study reward-related OFC responses and how they relate to behavioral dysfunction in ADHD. During fMRI data acquisition, participants performed a simple decision-making task, allowing us to image expectation-related responses to small and large monetary outcomes. Across all participants, we observed significant signal increases to large versus small expected rewards in the OFC. These responses were significantly enhanced in ADHD relative to TD participants. Moreover, stronger reward-related activity was correlated with individual differences in hyperactive/impulsive symptoms in the ADHD group, whereas high cognitive ability was associated with normalized OFC responses. These results provide evidence for the importance of OFC dysfunctions in the neuropathology of ADHD, highlighting the role of OFC-dependent goal-directed control mechanisms in this disorder.SIGNIFICANCE STATEMENT Attention-deficit/hyperactivity disorder (ADHD) is characterized by alterations in motivated behavior which can be understood as diminished goal-directed control. The orbitofrontal cortex (OFC) plays a key role in controlling goal-directed behavior, but its potential contribution to ADHD symptomatology remains poorly understood. Using high-resolution fMRI, we show that adolescent ADHD patients display enhanced OFC signaling of future rewards and that these increased reward-related responses are correlated with the severity of hyperactivity/impulsivity. These findings suggest that an inability to adequately evaluate future outcomes may translate into maladaptive behavior in ADHD patients. They also challenge the idea that dysfunctions in dopaminergic brain areas are the sole contributor to reward-related symptoms in ADHD and point to a central contribution of goal-directed control circuits in hyperactivity.

Population receptive field and connectivity properties of the early visual cortex in human albinism.

In albinism, the pathological decussation of the temporal retinal afferents at the optic chiasm leads to superimposed representations of opposing hemifields in the visual cortex. Here, we assessed the equivalence of the two representations and the cortico-cortical connectivity of the early visual areas. Applying fMRI-based population receptive field (pRF)-mapping (both hemifield and bilateral mapping) and connective field (CF)-modeling, we investigated the early visual cortex in 6 albinotic participants and 4 controls. In albinism, superimposed retinotopic representations of the contra- and ipsilateral visual hemifield were observed on the hemisphere contralateral to the stimulated eye. This was confirmed by the observation of bilateral pRFs during bilateral mapping. Hemifield mapping revealed similar pRF-sizes for both hemifield representations throughout V1 to V3. The typical increase of V1-sampling extent for V3 compared to V2 was not found for the albinotic participants. The similarity of the pRF-sizes for opposing visual hemifield representations highlights the equivalence of the two maps in the early visual cortex. The altered V1-sampling extent in V3 might indicate the adaptation of cortico-cortical connections to visual pathway abnormalities in albinism. These findings thus suggest that conservative developmental mechanisms are complemented by alterations of the extrastriate cortico-cortical connectivity.

In vivo MRI assessment of the human locus coeruleus along its rostrocaudal extent in young and older adults.

The locus coeruleus (LC), a major origin of noradrenergic projections in the central nervous system (CNS), may serve a critical role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD). As such, there is considerable interest to develop magnetic resonance imaging (MRI) techniques to assess the integrity of the LC in vivo. The high neuromelanin content of the LC serves as an endogenous contrast for MRI but existing protocols suffer from low spatial resolution along the rostrocaudal axis of the LC rendering it difficult to differentiate its integrity in caudal and rostral portions. This study presents a novel approach to investigate the human LC in vivo using T1-weighted Fast Low Angle Shot (FLASH) MRI at 3 T (T). Using high-resolution isotropic imaging to minimise the effect of low spatial resolution in the slice direction, this study aimed to characterise the rostrocaudal distribution of LC signal intensity attributed to neuromelanin from 25 young (22-30) and 57 older (61-80) adults. We found a significant age-related increase in maximum but not median signal intensity, indicating age-related differences were not homogenous. Instead, they were confined to the rostral third of the LC with relative sparing of the caudal portion. The findings presented demonstrate in vivo T1-weighted FLASH imaging may be used to characterise signal intensity changes across the entire rostrocaudal length of the LC (a corresponding standardised LC map is available for download), which may help to identify how the human LC is differentially affected in aging and neurodegenerative disease.

Impact of chiasma opticum malformations on the organization of the human ventral visual cortex.

Congenital malformations of the optic chiasm, such as enhanced and reduced crossing of the optic nerve fibers, are evident in albinism and achiasma, respectively. In early visual cortex the resulting additional visual input from the ipsilateral visual hemifield is superimposed onto the normal retinotopic representation of the contralateral visual field, which is likely due to conservative geniculo-striate projections. Counterintuitively, this organization in early visual cortex does not have profound consequences on visual function. Here we ask, whether higher stages of visual processing provide a correction to the abnormal representation allowing for largely normal perception. To this end we assessed the organization patterns of early and ventral visual cortex in five albinotic, one achiasmic, and five control participants. In albinism and achiasma the mirror-symmetrical superposition of the ipsilateral and contalateral visual fields was evident not only in early visual cortex, but also in the higher areas of the ventral processing stream. Specifically, in the visual areas VO1/2 and PHC1/2 no differences in the extent, the degree of superposition, and the magnitude of the responses were evident in comparison to the early visual areas. Consequently, the highly atypical organization of the primary visual cortex was propagated downstream to highly specialized processing stages in an undiminished and unchanged manner. This indicates largely unaltered cortico-cortical connections in both types of misrouting, i.e., enhanced and reduced crossing of the optic nerves. It is concluded that main aspects of visual function are preserved despite sizable representation abnormalities in the ventral visual processing stream.

Direct targeting of the thalamic anteroventral nucleus for deep brain stimulation by T1-weighted magnetic resonance imaging at 3 T.

BACKGROUND: The thalamic anteroventral nucleus (AV) is a promising target structure for deep brain stimulation (DBS) in patients suffering from refractory epilepsy. Direct visualization of the AV would improve spatial accuracy in functional stereotactic neurosurgery for treatment of this disease. METHODS: On 3-tesla magnetic resonance imaging (MRI), acquisition parameters were adjusted for optimal demarcation of the AV in 1 healthy subject. Reliability of AV visualization was then evaluated in 5 healthy individuals and 3 patients with refractory epilepsy. RESULTS: In all individuals, an adjusted T1-weighted sequence allowed for demarcation of the AV. It was clearly distinguishable from hyperintense myelin-rich lamellae surrounding it ventrally and laterally and appeared hypo-intense compared to the adjacent thalamic nuclei. Image resolution and contrast facilitated direct stereotactic targeting of the AV prior to DBS surgery in all 3 patients. CONCLUSIONS: Direct targeting of the AV can be achieved, which has immediate implications for the accuracy of MRI-guided DBS in patients with refractory epilepsy.

Long-term cortisol stress response in depression and comorbid anxiety is linked with reduced N-acetylaspartate in the anterior cingulate cortex.

OBJECTIVES: Major Depression (MDD) and anxiety disorders are stress-related disorders that share pathophysiological mechanisms. There is evidence for alterations of glutamate-glutamine, N-acetylaspartate (NAA) and GABA in the anterior cingulate cortex (ACC), a stress-sensitive region affected by hypothalamic-pituitary-adrenal axis (HPA). The aim was to investigate metabolic alterations in the ACC and whether hair cortisol, current stress or early life adversity predict them. METHODS: We investigated 22 patients with MDD and comorbid anxiety disorder and 23 healthy controls. Proton magnetic resonance spectroscopy was performed with voxels placed in pregenual (pg) and dorsal (d) ACC in 3 T. Analysis of hair cortisol was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: The N-acetylaspartate/Creatin ratio (NAA/Cr) was reduced in patients in both pgACC (p = .040) and dACC (p = .016). A significant interactive effect of diagnosis and cortisol on both pg-NAA/Cr (F = 5.00, p = .033) and d-NAA/Cr (F = 7.86, p = .009) was detected, whereby in controls cortisol was positively correlated with d-NAA/Cr (r = 0.61, p = .004). CONCLUSIONS: Our results suggest a relationship between NAA metabolism in ACC and HPA axis activity as represented by long-term cortisol output.

Achromatopsia-Visual Cortex Stability and Plasticity in the Absence of Functional Cones.

Purpose: Achromatopsia is a rare inherited disorder rendering retinal cone photoreceptors nonfunctional. As a consequence, the sizable foveal representation in the visual cortex is congenitally deprived of visual input, which prompts a fundamental question: is the cortical representation of the central visual field in patients with achromatopsia remapped to take up processing of paracentral inputs? Such remapping might interfere with gene therapeutic treatments aimed at restoring cone function. Methods: We conducted a multicenter study to explore the nature and plasticity of vision in the absence of functional cones in a cohort of 17 individuals affected by autosomal recessive achromatopsia and confirmed biallelic disease-causing CNGA3 or CNGB3 mutations. Specifically, we tested the hypothesis of foveal remapping in human achromatopsia. For this purpose, we applied two independent functional magnetic resonance imaging (fMRI)-based mapping approaches, i.e. conventional phase-encoded eccentricity and population receptive field mapping, to separate data sets. Results: Both fMRI approaches produced the same result in the group comparison of achromatopsia versus healthy controls: sizable remapping of the representation of the central visual field in the primary visual cortex was not apparent. Conclusions: Remapping of the cortical representation of the central visual field is not a general feature in achromatopsia. It is concluded that plasticity of the human primary visual cortex is less pronounced than previously assumed. A pretherapeutic imaging workup is proposed to optimize interventions.

Performance-related increases in hippocampal N-acetylaspartate (NAA) induced by spatial navigation training are restricted to BDNF Val homozygotes.

Recent evidence indicates experience-dependent brain volume changes in humans, but the functional and histological nature of such changes is unknown. Here, we report that adult men performing a cognitively demanding spatial navigation task every other day over 4 months display increases in hippocampal N-acetylaspartate (NAA) as measured with magnetic resonance spectroscopy. Unlike measures of brain volume, changes in NAA are sensitive to metabolic and functional aspects of neural and glia tissue and unlikely to reflect changes in microvasculature. Training-induced changes in NAA were, however, absent in carriers of the Met substitution in the brain-derived neurotrophic factor (BDNF) gene, which is known to reduce activity-dependent secretion of BDNF. Among BDNF Val homozygotes, increases in NAA were strongly related to the degree of practice-related improvement in navigation performance and normalized to pretraining levels 4 months after the last training session. We conclude that changes in demands on spatial navigation can alter hippocampal NAA concentrations, confirming epidemiological studies suggesting that mental experience may have direct effects on neural integrity and cognitive performance. BDNF genotype moderates these plastic changes, in line with the contention that gene-context interactions shape the ontogeny of complex phenotypes.

Structural changes to primary visual cortex in the congenital absence of cone input in achromatopsia.

Autosomal recessive Achromatopsia (ACHM) is a rare inherited disorder associated with dysfunctional cone photoreceptors resulting in a congenital absence of cone input to visual cortex. This might lead to distinct changes in cortical architecture with a negative impact on the success of gene augmentation therapies. To investigate the status of the visual cortex in these patients, we performed a multi-centre study focusing on the cortical structure of regions that normally receive predominantly cone input. Using high-resolution T1-weighted MRI scans and surface-based morphometry, we compared cortical thickness, surface area and grey matter volume in foveal, parafoveal and paracentral representations of primary visual cortex in 15 individuals with ACHM and 42 normally sighted, healthy controls (HC). In ACHM, surface area was reduced in all tested representations, while thickening of the cortex was found highly localized to the most central representation. These results were comparable to more widespread changes in brain structure reported in congenitally blind individuals, suggesting similar developmental processes, i.e., irrespective of the underlying cause and extent of vision loss. The cortical differences we report here could limit the success of treatment of ACHM in adulthood. Interventions earlier in life when cortical structure is not different from normal would likely offer better visual outcomes for those with ACHM.

Structural Differences Across Multiple Visual Cortical Regions in the Absence of Cone Function in Congenital Achromatopsia.

Most individuals with congenital achromatopsia (ACHM) carry mutations that affect the retinal phototransduction pathway of cone photoreceptors, fundamental to both high acuity vision and colour perception. As the central fovea is occupied solely by cones, achromats have an absence of retinal input to the visual cortex and a small central area of blindness. Additionally, those with complete ACHM have no colour perception, and colour processing regions of the ventral cortex also lack typical chromatic signals from the cones. This study examined the cortical morphology (grey matter volume, cortical thickness, and cortical surface area) of multiple visual cortical regions in ACHM (n = 15) compared to normally sighted controls (n = 42) to determine the cortical changes that are associated with the retinal characteristics of ACHM. Surface-based morphometry was applied to T1-weighted MRI in atlas-defined early, ventral and dorsal visual regions of interest. Reduced grey matter volume in V1, V2, V3, and V4 was found in ACHM compared to controls, driven by a reduction in cortical surface area as there was no significant reduction in cortical thickness. Cortical surface area (but not thickness) was reduced in a wide range of areas (V1, V2, V3, TO1, V4, and LO1). Reduction in early visual areas with large foveal representations (V1, V2, and V3) suggests that the lack of foveal input to the visual cortex was a major driving factor in morphological changes in ACHM. However, the significant reduction in ventral area V4 coupled with the lack of difference in dorsal areas V3a and V3b suggest that deprivation of chromatic signals to visual cortex in ACHM may also contribute to changes in cortical morphology. This research shows that the congenital lack of cone input to the visual cortex can lead to widespread structural changes across multiple visual areas.

Visuo-motor integration in humans: cortical patterns of response lateralisation and functional connectivity.

PURPOSE: We assessed response and functional connectivity patterns of different parts of the visual and motor cortices during visuo-motor integration with particular focus on the intraparietal sulcus (IPS). METHODS: Brain activity was measured during a visuo-motor task in 14 subjects using event-related fMRI. During central fixation, a blue or red target embedded in an array of grey distractors was presented for 250 ms in either the left or right visual hemifield. After a delay, the subjects were prompted to press the upper or lower response button for targets in the upper and lower hemifield with the left or right thumb for blue and red targets, respectively. The fMRI responses were evaluated for different regions of interests (ROIs), and the functional connectivity of the IPS subregions with these ROIs was quantified. RESULTS: In an anterior IPS region and a region in the anterior premotor cortex, presumably the frontal eye fields (FEF), visually driven responses were dominant contralateral to both visual stimulus and effector. Thus, the anterior IPS combines, in contrast to the posterior IPS and the occipital cortex, response properties of cortex activated by visual input and by motor output. Further, functional connectivity with the motor areas was stronger for the anterior than for the posterior IPS regions. DISCUSSION: Anterior IPS and FEF appear to be of major relevance for relating visual and effector information during visuo-motor integration. Patient studies with the devised paradigm are expected to uncover the impact of pathophysiologies and plasticity on the observed cortical lateralisation patterns.

Locus coeruleus MRI contrast is reduced in Alzheimer's disease dementia and correlates with CSF Aß levels.

INTRODUCTION: This study aimed to assess how interindividual differences in locus coeruleus (LC) magnetic resonance imaging (MRI) contrast relate to cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD). METHODS: LC MRI contrast was quantified in 73 individuals from the DZNE Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study comprising 25 healthy elderly adults and 21 individuals with subjective cognitive decline, 16 with mild cognitive impairment, and 11 participants with AD dementia using 3D T1-weighted fast low-angle shot (FLASH) imaging (0.75 mm isotropic resolution). Bootstrapped Pearson's correlations between LC contrast, CSF amyloid, and tau were performed in 44 individuals with CSF biomarker status. RESULTS: A significant regional decrease in LC MRI contrast was observed in patients with AD dementia but not mild cognitive impairment and subjective cognitive decline compared with healthy controls. A negative association between LC MRI contrast and levels of CSF amyloid but not with CSF tau was found. DISCUSSION: These results provide first evidence for a direct association between LC MRI contrast using in vivo T1-weighted FLASH imaging and AD pathology.

Audiovisual temporal correspondence modulates human multisensory superior temporal sulcus plus primary sensory cortices.

The brain should integrate related but not unrelated information from different senses. Temporal patterning of inputs to different modalities may provide critical information about whether those inputs are related or not. We studied effects of temporal correspondence between auditory and visual streams on human brain activity with functional magnetic resonance imaging (fMRI). Streams of visual flashes with irregularly jittered, arrhythmic timing could appear on right or left, with or without a stream of auditory tones that coincided perfectly when present (highly unlikely by chance), were noncoincident with vision (different erratic, arrhythmic pattern with same temporal statistics), or an auditory stream appeared alone. fMRI revealed blood oxygenation level-dependent (BOLD) increases in multisensory superior temporal sulcus (mSTS), contralateral to a visual stream when coincident with an auditory stream, and BOLD decreases for noncoincidence relative to unisensory baselines. Contralateral primary visual cortex and auditory cortex were also affected by audiovisual temporal correspondence or noncorrespondence, as confirmed in individuals. Connectivity analyses indicated enhanced influence from mSTS on primary sensory areas, rather than vice versa, during audiovisual correspondence. Temporal correspondence between auditory and visual streams affects a network of both multisensory (mSTS) and sensory-specific areas in humans, including even primary visual and auditory cortex, with stronger responses for corresponding and thus related audiovisual inputs.

Endoscopic eye tracking system for fMRI.

Here we introduce a new video-based real-time eye tracking system suitable for functional magnetic resonance imaging (fMRI) application. The described system monitors the subject's eye, which is illuminated with infrared light, directly at the headcoil using an endoscopic fibre optical system. This endoscopic technique assures reliable, easy-to-use and fast adjustment. It requires only a minimal amount of equipment at the headcoil and inside the examination room. Moreover, the short distance between the image acquisition optics and the eye provides high spatial tracking resolution. Interference from physiological head movement is effectively reduced by simultaneous tracking of both eye and head movements.

Atypical hemispheric dominance for attention: functional MRI topography.

The right hemisphere is predominantly involved in tasks associated with spatial attention. However, left hemispheric dominance for spatial attention can be found in healthy individuals, and both spatial attention and language can be lateralized to the same hemisphere. Little is known about the underlying regional distribution of neural activation in these 'atypical' individuals. Previously a large number of healthy subjects were screened for hemispheric dominance of visuospatial attention and language, using functional Doppler ultrasonography. From this group, subjects were chosen who were 'atypical' for hemispheric dominance of visuospatial attention and language, and their pattern of brain activation was studied with functional magnetic resonance imaging during a task probing spatial attention. Right-handed subjects with the 'typical' pattern of brain organization served as control subjects. It was found that subjects with an inverted lateralization of language and spatial attention (language right, attention left) recruited left-hemispheric areas in the attention task, homotopic to those recruited by control subjects in the right hemisphere. Subjects with lateralization of both language and attention to the right hemisphere activated an attentional network in the right hemisphere that was comparable to control subjects. The present findings suggest that not the hemispheric side, but the intrahemispheric pattern of activation is the distinct feature for the neural processes underlying language and attention.

Dominance for language and spatial processing: limited capacity of a single hemisphere.

Using functional magnetic resonance imaging during word generation and spatial judgement (Landmark task), we investigated how hemispheric specializations for language and spatial processing interact in healthy individuals. We found individuals with atypical, right-hemispheric dominance for language to have more bilateral activation during spatial judgement than individuals with typical, disjunct hemispheric specialization, that is, left dominance for language and right dominance for spatial tasks. These findings suggest that hemispheric specializations for language and spatial functions interfere to some extent and favour additional recruitment of the opposite hemispheres for spatial functions.

Magnetic resonance volumetry and spectroscopy of hippocampus and insula in relation to severe exposure of traumatic stress.

Severe and chronic stress affects the hippocampus, especially during development. However, studies concerning structural alterations of the hippocampus yielded a rather inconsistent picture. Moreover, further anxiety-relevant brain regions, such as the insula, might be implicated in the pathophysiology of posttraumatic stress disorder (PTSD). We combined magnetic resonance (MR) volumetric and spectroscopic analyses of hippocampus and insula in highly traumatized refugees without a history of alcohol/substance abuse or other comorbid diseases. No PTSD-related difference was apparent in the volumes or neurometabolite levels of bilateral hippocampus or insula. However, an association between left hippocampal N-acetyl-aspartate (NAA) and adverse childhood experiences indicated a potential detrimental effect of the early environment on hippocampal integrity. Our results add to increasing evidence that PTSD-related, morphological alterations in the hippocampus are a consequence of early adversity or may result from other factors, such as extensive use of alcohol.

Plasticity and stability of the visual system in human achiasma.

The absence of the optic chiasm is an extraordinary and extreme abnormality in the nervous system. The abnormality produces highly atypical functional responses in the cortex, including overlapping hemifield representations and bilateral population receptive fields in both striate and extrastriate visual cortex. Even in the presence of these large functional abnormalities, the effect on visual perception and daily life is not easily detected. Here, we demonstrate that in two achiasmic humans the gross topography of the geniculostriate and occipital callosal connections remains largely unaltered. We conclude that visual function is preserved by reorganization of intracortical connections instead of large-scale reorganizations of the visual cortex. Thus, developmental mechanisms of local wiring within cortical maps compensate for the improper gross wiring to preserve function in human achiasma.