Blood Oxygenation Level-dependent Amplitude Research Articles

Atopic dermatitis and stress: A functional magnetic resonance imaging study of female patients with atopic dermatitis using an arithmetic task

AbstractBackgroundAtopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by eczematous lesions, dry skin and persistent itch. AD may worsen due to psychological stress. However, little is known about the neural correlates that mediate the interaction between psychological stress and AD.ObjectivesTo identify the possible difference in brain activation during arithmetic‐task induced stress in patients with AD versus healthy controls (HC) as well as the link between the brain response and clinical and psychodemographic parameters.MethodsA cohort of 29 AD female patients and 23 matched HC were recruited to investigate the potential difference in functional magnetic resonance imaging (fMRI) response to a block‐designed arithmetic paradigm. Both the HC and AD subjects were evaluated regarding their psychological traits, and for the AD subjects also their clinical characteristics, including stress indicators such as heart rate and salivary cortisol. We employed both univariate and multivariate statistical methods to analyse the blood oxygen level dependent (BOLD) fMRI response of the subjects to the block‐designed arithmetic paradigm.Results(1) Compared with HC subjects, the AD patients depict less deactivation in the default mode network including right angular gyrus, bilateral temporal pole and temporal lobe in response to the arithmetic task. (2) The BOLD fMRI response amplitude in the right postcentral gyrus and inferior parietal lobule is positively correlated with the stress susceptibility scores in the AD subjects, whereas the trend was the opposite of this for the HC subjects. (3) The activation in the postcentral gyrus also shows a correlation with the degree of itch in the AD patients.ConclusionsThe BOLD fMRI measurements based on an arithmetic paradigm can provide useful insight into altered brain processing and its association with psychological traits and clinical characteristics in subjects with AD. Psychological stress exacerbates brain activities for the AD subjects in the motor, somatosensory association cortex, perception and sensory integration processing. The postcentral gyrus might be of particular interest for itch and stress.

GABAergic inhibition shapes behavior and neural dynamics in human visual working memory.

Neuronal inhibition, primarily mediated by GABAergic neurotransmission, is crucial for brain development and healthy cognition. Gamma-aminobutyric acid concentration levels in sensory areas have been shown to correlate with hemodynamic and oscillatory neuronal responses. How these measures relate to one another during working memory, a higher-order cognitive process, is still poorly understood. We address this gap by collecting magnetoencephalography, functional magnetic resonance imaging, and Flumazenil positron emission tomography data within the same subject cohort using an n-back working-memory paradigm. By probing the relationship between GABAA receptor distribution, neural oscillations, and Blood Oxygen Level Dependent (BOLD) modulations, we found that GABAA receptor density in higher-order cortical areas predicted the reaction times on the working-memory task and correlated positively with the peak frequency of gamma power modulations and negatively with BOLD amplitude. These findings support and extend theories linking gamma oscillations and hemodynamic responses to gamma-aminobutyric acid neurotransmission and to the excitation-inhibition balance and cognitive performance in humans. Considering the small sample size of the study, future studies should test whether these findings also hold for other, larger cohorts as well as to examine in detail how the GABAergic system and neural fluctuations jointly support working-memory task performance.

Microstructural white matter integrity in relation to vascular reactivity in Dutch-type hereditary cerebral amyloid angiopathy

Cerebral Amyloid Angiopathy (CAA) is characterized by cerebrovascular amyloid-β accumulation leading to hallmark cortical MRI markers, such as vascular reactivity, but white matter is also affected. By studying the relationship in different disease stages of Dutch-type CAA (D-CAA), we tested the relation between vascular reactivity and microstructural white matter integrity loss. In a cross-sectional study in D-CAA, 3 T MRI was performed with Blood-Oxygen-Level-Dependent (BOLD) fMRI upon visual activation to assess vascular reactivity and diffusion tensor imaging to assess microstructural white matter integrity through Peak Width of Skeletonized Mean Diffusivity (PSMD). We assessed the relationship between BOLD parameters – amplitude, time-to-peak (TTP), and time-to-baseline (TTB) – and PSMD, with linear and quadratic regression modeling. In total, 25 participants were included (15/10 pre-symptomatic/symptomatic; mean age 36/59 y). A lowered BOLD amplitude (unstandardized β = 0.64, 95%CI [0.10, 1.18], p = 0.02, Adjusted R2 = 0.48), was quadratically associated with increased PSMD levels. A delayed BOLD response, with prolonged TTP (β = 8.34 × 10−6, 95%CI [1.84 × 10−6, 1.48 × 10−5], p = 0.02, Adj. R2 = 0.25) and TTB (β = 6.57 × 10−6, 95%CI [1.92 × 10−6, 1.12 × 10−5], p = 0.008, Adj. R2 = 0.29), was linearly associated with increased PSMD. In D-CAA subjects, predominantly in the symptomatic stage, impaired cerebrovascular reactivity is related to microstructural white matter integrity loss. Future longitudinal studies are needed to investigate whether this relation is causal.

Modeling venous bias in resting state functional MRI metrics.

Resting-state (rs) functional magnetic resonance imaging (fMRI) is used to detect low-frequency fluctuations in the blood oxygen-level dependent (BOLD) signal across brain regions. Correlations between temporal BOLD signal fluctuations are commonly used to infer functional connectivity. However, because BOLD is based on the dilution of deoxyhemoglobin, it is sensitive to veins of all sizes, and its amplitude is biased by draining veins. These biases affect local BOLD signal location and amplitude, and may also influence BOLD-derived connectivity measures, but the magnitude of this venous bias and its relation to vein size and proximity is unknown. Here, veins were identified using high-resolution quantitative susceptibility maps and utilized in a biophysical model to investigate systematic venous biases on common local rsfMRI-derived measures. Specifically, we studied the impact of vein diameter and distance to veins on the amplitude of low-frequency fluctuations (ALFF), fractional ALFF (fALFF), Hurst exponent (HE), regional homogeneity (ReHo), and eigenvector centrality values in the grey matter. Values were higher across all distances in smaller veins, and decreased with increasing vein diameter. Additionally, rsfMRI values associated with larger veins decrease with increasing distance from the veins. ALFF and ReHo were the most biased by veins, while HE and fALFF exhibited the smallest bias. Across all metrics, the amplitude of the bias was limited in voxel-wise data, confirming that venous structure is not the dominant source of contrast in these rsfMRI metrics. Finally, the models presented can be used to correct this venous bias in rsfMRI metrics.

Functional imaging and neurochemistry identify in vivo neuroprotection mechanisms counteracting excitotoxicity and neurovascular changes in the hippocampus and visual cortex of obese and type 2 diabetic animal models.

Functional MRI (fMRI) with 1 H-MRS was combined on the hippocampus and visual cortex of animal models of obesity (high-fat diet, HFD) and type 2 diabetes (T2D) to identify the involvedmechanisms and temporal evolution of neurometabolic changes in these disorders that could serve as potentially reliable clinical biomarkers. HFD rats presented elevated levels of N-acetylaspartylglutamate (NAAG) (p = 0.0365 vs. standard diet, SD) and glutathione (GSH) (p = 0.0494 vs. SD) in the hippocampus. NAAG and GSH levels in this structure proved to be correlated (r = 0.4652, p = 0.0336). This mechanism was not observed in diabetic rats. Combining MRS and fMRI-evaluated blood-oxygen-level-dependent (BOLD) response, elevated taurine (p = 0.0326 vs. HFD) and GABA type A receptor (GABAA R) (p = 0.0211 vs. SD and p = 0.0153 vs. HFD) were observed in the visual cortex of only diabetic rats, counteracting the elevated BOLD responseand suggesting an adaptative mechanism against hyperexcitability observed in the primary visual cortex (V1) (p = 0.0226 vs. SD). BOLD amplitude was correlated with the glutamate levels (r = 0.4491; p = 0.0316). Therefore, here we found evidence for several biological dichotomies regarding excitotoxicity and neuroprotection in different brain regions, identifying putative markers of their different susceptibility and response to the metabolic and vascular insults of obesity and diabetes.

Action-based predictions affect visual perception, neural processing, and pupil size, regardless of temporal predictability

Sensory consequences of one's own action are often perceived as less intense, and lead to reduced neural responses, compared to externally generated stimuli. Presumably, such sensory attenuation is due to predictive mechanisms based on the motor command (efference copy). However, sensory attenuation has also been observed outside the context of voluntary action, namely when stimuli are temporally predictable. Here, we aimed at disentangling the effects of motor and temporal predictability-based mechanisms on the attenuation of sensory action consequences. During fMRI data acquisition, participants (N = 25) judged which of two visual stimuli was brighter. In predictable blocks, the stimuli appeared temporally aligned with their button press (active) or aligned with an automatically generated cue (passive). In unpredictable blocks, stimuli were presented with a variable delay after button press/cue, respectively. Eye tracking was performed to investigate pupil-size changes and to ensure proper fixation. Self-generated stimuli were perceived as darker and led to less neural activation in visual areas than their passive counterparts, indicating sensory attenuation for self-generated stimuli independent of temporal predictability. Pupil size was larger during self-generated stimuli, which correlated negatively with the blood oxygenation level dependent (BOLD) response: the larger the pupil, the smaller the BOLD amplitude in visual areas. Our results suggest that sensory attenuation in visual cortex is driven by action-based predictive mechanisms rather than by temporal predictability. This effect may be related to changes in pupil diameter. Altogether, these results emphasize the role of the efference copy in the processing of sensory action consequences.

The association between language-based task-functional magnetic resonance imaging hemodynamics and baseline GABA+ and glutamate-glutamine measured in pre-supplementary motor area: A pilot study in an aging model.

Aging is a natural phenomenon that elicits slow and progressive cerebrovascular and neurophysiological changes that eventually lead to cognitive decline. The objective of this pilot study is to examine the association of GABA+ and glutamate–glutamine (Glx) complex with language-based blood oxygen level dependent (BOLD) hemodynamics in an aging model. More specifically, using standard BOLD we will first attempt to validate whether previously reported findings for BOLD amplitude and resting neurochemical relationships hold in an aging model. Secondly, we will investigate how our recently established neurosensitized task-BOLD energetics relate to resting GABA+ and Glx, especially accounting for titration of task difficulty. To support the above endeavors, we optimize the baseline fitting for edited magnetic resonance spectroscopy (MRS) difference spectra to sensitize GABA+ and Glx concentrations to aging-related differences. We identify a spline-knot spacing of 0.6ppm to yield the optimal aging-related differences in GABA+ and Glx. The optimized MRS values were then graduated to relate to task-BOLD hemodynamics. Our results did not replicate previous findings that relate task-BOLD amplitude and resting GABA+ and Glx. However, we did identify neurochemistry relationships with the vascularly-driven dispersion component of the hemodynamic response function, specifically in older participants. In terms of neuro-sensitized BOLD energetics and the underlying role of GABA+ and Glx, our data suggests that the task demands are supported by both neurometabolites depending on the difficulty of the task stimuli. Another novelty is that we developed task-based functional parcellation of pre-SMA using both groups. In sum, we are the first to demonstrate that multimodal task-fMRI and MRS studies are beneficial to improve our understanding of the aging brain physiology, and to set the platform to better inform approaches for clinical care in aging-related neurovascular diseases. We also urge future studies to replicate our findings in a larger population incorporating a lifespan framework.

Aging Effect, Reproducibility, and Test-Retest Reliability of a New Cerebral Amyloid Angiopathy MRI Severity Marker-Cerebrovascular Reactivity to Visual Stimulation.

Decreased cerebrovascular reactivity, measured as changes in blood-oxygen-level-dependent (BOLD) signal, is a potential new cerebral amyloid angiopathy (CAA) severity marker. Before clinical application, the effect of aging on BOLD parameters, and reproducibility and test-retest reliability of these parameters should be assessed. Assess the effect of healthy aging on cerebrovascular reactivity (BOLD amplitude, time to peak, and time to baseline). And determine reproducibility and test-retest reliability of these parameters. Prospective-observational. Eighty-six healthy adults (mean age 56 years, 55% female), 10 presymptomatic D-CAA mutation carriers (mean age 34 years, 70% female), and 10 symptomatic D-CAA mutation carriers (mean age 54 years, 70% female). 3-T, three-dimensional (3D) T1-weighted MRI and gradient echo BOLD fMRI. To assess test-retest reliability of BOLD parameters, i.e. BOLD amplitude, time to peak, and time to baseline, BOLD fMRI scans were repeated three times immediately after each other, in both controls and mutation carriers. To assess reproducibility, BOLD fMRI scans were repeated with a 3-week interval for each subject. Linear regression analyses and two-way mixed absolute agreement intra-class correlation approach. Healthy aging was associated with decreased BOLD amplitude (β=-0.711) and prolonged time to baseline (β=0.236) in the visual cortex after visual stimulation Reproducibility of BOLD amplitude was excellent (ICC 0.940) in the subgroup of healthy adults. Test-retest reliability for BOLD amplitude was excellent in healthy adults (ICC 0.856-0.910) and presymptomatic D-CAA mutation carriers (ICC 0.959-0.981). In symptomatic D-CAA mutation carriers, test-retest reliability was poor for all parameters (ICCs < 0.5). Healthy aging is associated with decreased cerebrovascular reactivity, measured by changes in BOLD response to visual stimulation. The BOLD amplitude appears to be a robust measurement in healthy adults and presymptomatic D-CAA mutation carriers, but not in symptomatic D-CAA mutation carriers.

Neural correlates of repeated retrieval of emotional autobiographical events

Understanding the neural correlates of repetitive retrieval of emotional events is critical in addressing pathological emotional processing, as repeated processing is central for a number of different therapeutic interventions. In the current study, single-trial functional brain activity was assessed in key regions implicated in episodic retrieval, including the medial prefrontal cortex (mPFC), anterior hippocampus, posterior hippocampus, and the posteromedial parietal cortex (i.e., posterior cingulate cortex and the precuneus) following repeated retrieval of pleasant and unpleasant autobiographical events. Replicating previous studies, repetition prompted reduced blood-oxygen-level-dependent (BOLD) amplitude in the anterior hippocampus and the mPFC, but not in the posterior hippocampus, due to no functional activity during mental imagery, or in the posteromedial parietal cortex, due to enhanced activation that was sustained across repetitions. Neural activation during pleasant and unpleasant autobiographical retrieval did not differ as a function of repetition, indicating similar processing effects regardless of motivational relevance. Taken together, the hedonic valence of retrieved memories does not affect functional activity associated with repeated retrieval of episodic events, in which the pattern of BOLD amplitude change suggests a dissociation between the hippocampal-prefrontal circuit, which shows repetition suppression, and the posteromedial parietal cortex, which shows sustained activation.

Neural response during temporal - and spatial luminance contrast processing and its manifestation in the blood-oxygen-level-dependent-signal in striate and extra-striate cortex.

The primate visual system has been the prime site for investigating the relationship between stimulus property, neural response and blood-oxygen-level-dependent (BOLD)-signal; yet this relationship remains ill-understood. Electrophysiological studies have shown that the ability to visualise a neural response is determined by stimulus property and presentation paradigm. The neural response in the human visual cortex consists of a phasic response processing temporal and tonic response processing spatial luminance contrast. We investigated their influence on the BOLD signal from the visual cortex. To do so, we compared BOLD signal amplitude from BA17 and BA18 of 15 human volunteers to visual patterns varying the size of the active neural population and the discharge activity of this population. The BOLD signal amplitude in both areas reflected the discharge activity of the active neural population but not the size of the active neural population. For identical stimuli, BOLD signal amplitude in BA17 exceeded than that of BA18. This indicates that the BOLD signal reflects the tonic neural neuronal response during spatial luminance contrast processing. The difference in BOLD signal amplitude between BA17 and BA18 is accounted for by differences in neurophysiological and cytoarchitectonic differences between the two areas. Our findings offer an understanding of the relationship between stimulus property, neural response and the BOLD signal by considering the cytoarchitectonic, and neurophysiological make-up between different cortical areas and the influence of a phasic and tonic neural response on local deoxyhaemoglobin concentration. Conversely, differences in BOLD signal between brain structures and stimuli provide cues to the influence of different neurophysiological mechanisms on the neural response.

Sub-millimetre resolution laminar fMRI using Arterial Spin Labelling in humans at 7 T.

Laminar fMRI at ultra-high magnetic field strength is typically carried out using the Blood Oxygenation Level-Dependent (BOLD) contrast. Despite its unrivalled sensitivity to detecting activation, the BOLD contrast is limited in its spatial specificity due to signals stemming from intra-cortical ascending and pial veins. Alternatively, regional changes in perfusion (i.e., cerebral blood flow through tissue) are colocalised to neuronal activation, which can be non-invasively measured using Arterial Spin Labelling (ASL) MRI. In addition, ASL provides a quantitative marker of neuronal activation in terms of perfusion signal, which is simultaneously acquired along with the BOLD signal. However, ASL for laminar imaging is challenging due to the lower SNR of the perfusion signal and higher RF power deposition i.e., specific absorption rate (SAR) of ASL sequences. In the present study, we present for the first time in humans, isotropic sub-millimetre spatial resolution functional perfusion images using Flow-sensitive Alternating Inversion Recovery (FAIR) ASL with a 3D-EPI readout at 7 T. We show that robust statistical activation maps can be obtained with perfusion-weighting in a single session. We observed the characteristic BOLD amplitude increase towards the superficial laminae, and, in apparent discrepancy, the relative perfusion profile shows a decrease of the amplitude and the absolute perfusion profile a much smaller increase towards the cortical surface. Considering the draining vein effect on the BOLD signal using model-based spatial “convolution”, we show that the empirically measured perfusion and BOLD profiles are, in fact, consistent with each other. This study demonstrates that laminar perfusion fMRI in humans is feasible at 7 T and that caution must be exercised when interpreting BOLD signal laminar profiles as direct representation of the cortical distribution of neuronal activity.

Cerebrovascular reactivity in cerebral amyloid angiopathy, Alzheimer disease, and mild cognitive impairment.

To assess cerebrovascular reactivity in response to a visual task in participants with cerebral amyloid angiopathy (CAA), Alzheimer disease (AD), and mild cognitive impairment (MCI) using fMRI. This prospective cohort study included 40 patients with CAA, 22 with AD, 27 with MCI, and 25 healthy controls. Each participant underwent a visual fMRI task using a contrast-reversing checkerboard stimulus. Visual evoked potentials (VEPs) were used to compare visual cortex neuronal activity in 83 participants. General linear models using least-squares means, adjusted for multiple comparisons with the Tukey test, were used to estimate mean blood oxygen level-dependent (BOLD) signal change during the task and VEP differences between groups. After adjustment for age and hypertension, estimated mean BOLD response amplitude was as follows: CAA 1.88% (95% confidence interval [CI] 1.60%-2.15%), AD 2.26% (1.91%-2.61%), MCI 2.15% (1.84%-2.46%), and control 2.65% (2.29%-3.00%). Only patients with CAA differed from controls (p = 0.01). In the subset with VEPs, group was not associated with prolonged latencies or lower amplitudes. Lower BOLD amplitude response was associated with higher white matter hyperintensity (WMH) volumes in CAA (for each 0.1% lower BOLD response amplitude, the WMH volume was 9.2% higher, 95% CI 6.0%-12.4%) but not other groups (p = 0.002 for interaction) when controlling for age and hypertension. Mean visual BOLD response amplitude was lowest in participants with CAA compared to controls, without differences in VEP latencies and amplitudes. This suggests that the impaired visual BOLD response is due to reduced vascular reactivity in CAA. In contrast to participants with CAA, the visual BOLD response amplitude did not differ between those with AD or MCI and controls.

Is the Blood Oxygenation Level-Dependent fMRI Response to Motor Tasks Altered in Children After Neonatal Stroke?

Functional MRI is increasingly being used in the assessment of brain activation and connectivity following stroke. Many of these studies rely on the Blood Oxygenation Level Dependent (BOLD) contrast. However, the stability, as well as the accuracy of the BOLD response to motor task in the ipsilesional hemisphere, remains ambiguous. In this work, the BOLD signal acquired from both healthy and affected hemispheres was analyzed in 7-year-old children who sustained a Neonatal Arterial Ischemic Stroke (NAIS). Accordingly, a repetitive motor task of the contralesional and the ipsilesional hands was performed by 33 patients with unilateral lesions. These patients were divided into two groups: those without cerebral palsy (NAIS), and those with cerebral palsy (CP). The BOLD signal time course was obtained from distinctly defined regions of interest (ROIs) extracted from the functional activation maps of 30 healthy controls with similar age and demographic characteristics as the patients. An ROI covering both the primary motor cortex (M1) and the primary somatosensory cortex (S1) was also tested. Compared with controls, NAIS patients without CP had similar BOLD amplitude variation for both the contralesional and the ipsilesional hand movements. However, in the case of NAIS patients with CP, a significant difference in the averaged BOLD amplitude was found between the healthy and affected hemisphere. In both cases, no progressive attenuation of the BOLD signal amplitude was observed throughout the task epochs. Besides, results also showed a correlation between the BOLD signal percentage variation of the lesioned hemisphere and the dexterity level. These findings suggest that for patients who sustained a NAIS with no extensive permanent motor impairment, BOLD signal-based data analysis can be a valuable tool for the evaluation of functional brain networks.

Linear systems analysis for laminar fMRI: Evaluating BOLD amplitude scaling for luminance contrast manipulations

A fundamental assumption of nearly all functional magnetic resonance imaging (fMRI) analyses is that the relationship between local neuronal activity and the blood oxygenation level dependent (BOLD) signal can be described as following linear systems theory. With the advent of ultra-high field (7T and higher) MRI scanners, it has become possible to perform sub-millimeter resolution fMRI in humans. A novel and promising application of sub-millimeter fMRI is measuring responses across cortical depth, i.e. laminar imaging. However, the cortical vasculature and associated directional blood pooling towards the pial surface strongly influence the cortical depth-dependent BOLD signal, particularly for gradient-echo BOLD. This directional pooling may potentially affect BOLD linearity across cortical depth. Here we assess whether the amplitude scaling assumption for linear systems theory holds across cortical depth. For this, we use stimuli with different luminance contrasts to elicit different BOLD response amplitudes. We find that BOLD amplitude across cortical depth scales with luminance contrast, and that this scaling is identical across cortical depth. Although nonlinearities may be present for different stimulus configurations and acquisition protocols, our results suggest that the amplitude scaling assumption for linear systems theory across cortical depth holds for luminance contrast manipulations in sub-millimeter laminar BOLD fMRI.

Resting state fMRI reveals differential effects of glucose administration on central appetite signalling in young and old adults.

Healthy aging has been associated with reduced appetite and lower energy intake, which can lead to loss of bodyweight, undernutrition and related health problems. The causes for the decline in caloric intake are multifactorial, involving physiological and non-physiological processes. Here we examined the effect of glucose on brain function in healthy adults as well as age-related, physiological changes in brain responses associated with macronutrient intake. Using a randomized, double-blind, balanced cross-over design, younger (n = 16, aged 21-30) and older (n = 16, aged 55-78) adults received a drink containing glucose and a taste-matched placebo after an overnight fast. Blood glucose and hunger were assessed at baseline and 20 min post-ingestion, after which participants underwent resting state functional magnetic resonance imaging. Frequency-dependent changes associated with glucose administration in slow-5 (0.01-0.027 Hz) and slow-4 (0.027-0.073 Hz) amplitude of low-frequency fluctuations (ALFF) and fractional ALFF (fALFF) of the blood oxygen level-dependent (BOLD) signal were investigated within the young healthy adults, and then extended to the older age group. Consistent with previous reports, glucose decreased amplitude in slow-5 fALFF within the left orbitofrontal cortex and insular cortex in the young adults. We observed a significant interaction in slow-5 ALFF and fALFF in the left insula, such that younger participants showed a decrease in BOLD amplitude, whereas older participants showed an increase, after glucose administration. We further observed an interaction in slow-4 ALFF in the occipital region and precuneus, with older participants showing an increase in magnitude of slow-4 ALFF and younger participants showing a decrease in the same measure. These age-related, frequency-dependent changes in the magnitude of the BOLD signal in the insula, a key region related to energy homeostasis following feeding, may point to a change in satiety or homeostatic signalling contributing to behavioural changes in energy intake during senescence.

A widespread visually-sensitive functional network relates to symptoms in essential tremor.

Essential tremor is a neurological syndrome of heterogeneous pathology and aetiology that is characterized by tremor primarily in the upper extremities. This tremor is commonly hypothesized to be driven by a single or multiple neural oscillator(s) within the cerebello-thalamo-cortical pathway. Several studies have found an association of blood-oxygen level-dependent (BOLD) signal in the cerebello-thalamo-cortical pathway with essential tremor, but there is behavioural evidence that also points to the possibility that the severity of tremor could be influenced by visual feedback. Here, we directly manipulated visual feedback during a functional MRI grip force task in patients with essential tremor and control participants, and hypothesized that an increase in visual feedback would exacerbate tremor in the 4-12 Hz range in essential tremor patients. Further, we hypothesized that this exacerbation of tremor would be associated with dysfunctional changes in BOLD signal and entropy within, and beyond, the cerebello-thalamo-cortical pathway. We found that increases in visual feedback increased tremor in the 4-12 Hz range in essential tremor patients, and this increase in tremor was associated with abnormal changes in BOLD amplitude and entropy in regions within the cerebello-thalamo-motor cortical pathway, and extended to visual and parietal areas. To determine if the tremor severity was associated with single or multiple brain region(s), we conducted a birectional stepwise multiple regression analysis, and found that a widespread functional network extending beyond the cerebello-thalamo-motor cortical pathway was associated with changes in tremor severity measured during the imaging protocol. Further, this same network was associated with clinical tremor severity measured with the Fahn, Tolosa, Marin Tremor Rating Scale, suggesting this network is clinically relevant. Since increased visual feedback also reduced force error, this network was evaluated in relation to force error but the model was not significant, indicating it is associated with force tremor but not force error. This study therefore provides new evidence that a widespread functional network is associated with the severity of tremor in patients with essential tremor measured simultaneously at the hand during functional imaging, and is also associated with the clinical severity of tremor. These findings support the idea that the severity of tremor is exacerbated by increased visual feedback, suggesting that designers of new computing technologies should consider using lower visual feedback levels to reduce tremor in essential tremor.

Post-stimulus fMRI and EEG responses: Evidence for a neuronal origin hypothesised to be inhibitory

Post-stimulus undershoots, negative responses following cessation of stimulation, are widely observed in functional magnetic resonance (fMRI) blood oxygenation level dependent (BOLD) data. However, the debate surrounding whether the origin of this response phase is neuronal or vascular, and whether it provides functionally relevant information, that is additional to what is contained in the primary response, means that undershoots are widely overlooked. We simultaneously recorded electroencephalography (EEG), BOLD and cerebral blood-flow (CBF) [obtained from arterial spin labelled (ASL) fMRI] fMRI responses to hemifield checkerboard stimulation to test the potential neural origin of the fMRI post-stimulus undershoot. The post-stimulus BOLD and CBF signal amplitudes in both contralateral and ipsilateral visual cortex depended on the post-stimulus power of the occipital 8–13Hz (alpha) EEG neuronal activity, such that trials with highest EEG power showed largest fMRI undershoots in contralateral visual cortex. This correlation in post-stimulus EEG-fMRI responses was not predicted by the primary response amplitude. In the contralateral visual cortex we observed a decrease in both cerebral rate of oxygen metabolism (CMRO2) and CBF during the post-stimulus phase. In addition, the coupling ratio (n) between CMRO2 and CBF was significantly lower during the positive contralateral primary response phase compared with the post-stimulus phase and we propose that this reflects an altered balance of excitatory and inhibitory neuronal activity. Together our data provide strong evidence that the post-stimulus phase of the BOLD response has a neural origin which reflects, at least partially, an uncoupling of the neuronal responses driving the primary and post-stimulus responses, explaining the uncoupling of the signals measured in the two response phases. We suggest our results are consistent with inhibitory processes driving the post-stimulus EEG and fMRI responses. We therefore propose that new methods are required to model the post-stimulus and primary responses independently, enabling separate investigation of response phases in cognitive function and neurological disease.

Investigating the spatiotemporal characteristics of the deoxyhemoglobin-related and deoxyhemoglobin-unrelated functional hemodynamic response across cortical layers in awake marmosets

Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) has become a major tool to map neural activity. However, the spatiotemporal characteristics of the BOLD functional hemodynamic response across the cortical layers remain poorly understood. While human fMRI studies suffer from low spatiotemporal resolution, the use of anesthesia in animal models introduces confounding factors. Additionally, inflow contributions to the fMRI signal become non-negligible when short repetition times (TRs) are used. In the present work, we mapped the BOLD fMRI response to somatosensory stimulation in awake marmosets. To address the above technical concerns, we used a dual-echo gradient-recalled echo planar imaging (GR-EPI) sequence to separate the deoxyhemoglobin-related response (absolute T2* differences) from the deoxyhemoglobin-unrelated response (relative S0 changes). We employed a spatial saturation pulse to saturate incoming arterial spins and reduce inflow effects. Functional GR-EPI images were obtained from a single coronal slice with two different echo times (13.5 and 40.5ms) and TR=0.2s. BOLD, T2*, and S0 images were calculated and their functional responses were detected in both hemispheres of primary somatosensory cortex, from which five laminar regions (L1+2, L3, L4, L5, and L6) were derived. The spatiotemporal distribution of the BOLD response across the cortical layers was heterogeneous, with the middle layers having the highest BOLD amplitudes and shortest onset times. ΔT2* also showed a similar trend. However, functional S0 changes were detected only in L1+2, with a fast onset time. Because inflow effects were minimized, the source of S0 functional changes in L1+2 could be attributed to a reduction of cerebrospinal fluid volume fraction due to the functional increase in cerebral blood volume and to unmodeled T2* changes in the extra- and intra-venous compartments. Caution should be exercised when interpreting laminar BOLD fMRI changes in superficial layers as surrogates of underlying neural activity.

Reduced error signalling in medication-naive children with ADHD: associations with behavioural variability and post-error adaptations.

We examined the blood-oxygen level-dependent (BOLD) activation in brain regions that signal errors and their association with intraindividual behavioural variability and adaptation to errors in children with attention-deficit/hyperactivity disorder (ADHD). We acquired functional MRI data during a Flanker task in medication-naive children with ADHD and healthy controls aged 8-12 years and analyzed the data using independent component analysis. For components corresponding to performance monitoring networks, we compared activations across groups and conditions and correlated them with reaction times (RT). Additionally, we analyzed post-error adaptations in behaviour and motor component activations. We included 25 children with ADHD and 29 controls in our analysis. Children with ADHD displayed reduced activation to errors in cingulo-opercular regions and higher RT variability, but no differences of interference control. Larger BOLD amplitude to error trials significantly predicted reduced RT variability across all participants. Neither group showed evidence of post-error response slowing; however, post-error adaptation in motor networks was significantly reduced in children with ADHD. This adaptation was inversely related to activation of the right-lateralized ventral attention network (VAN) on error trials and to task-driven connectivity between the cingulo-opercular system and the VAN. Our study was limited by the modest sample size and imperfect matching across groups. Our findings show a deficit in cingulo-opercular activation in children with ADHD that could relate to reduced signalling for errors. Moreover, the reduced orienting of the VAN signal may mediate deficient post-error motor adaptions. Pinpointing general performance monitoring problems to specific brain regions and operations in error processing may help to guide the targets of future treatments for ADHD.

Longitudinal decrease in blood oxygenation level dependent response in cerebral amyloid angiopathy.

Lower blood oxygenation level dependent (BOLD) signal changes in response to a visual stimulus in functional magnetic resonance imaging (fMRI) have been observed in cross-sectional studies of cerebral amyloid angiopathy (CAA), and are presumed to reflect impaired vascular reactivity. We used fMRI to detect a longitudinal change in BOLD responses to a visual stimulus in CAA, and to determine any correlations between these changes and other established biomarkers of CAA progression. Data were acquired from 22 patients diagnosed with probable CAA (using the Boston Criteria) and 16 healthy controls at baseline and one year. BOLD data were generated from the 200 most active voxels of the primary visual cortex during the fMRI visual stimulus (passively viewing an alternating checkerboard pattern). In general, BOLD amplitudes were lower at one year compared to baseline in patients with CAA (p = 0.01) but were unchanged in controls (p = 0.18). The longitudinal difference in BOLD amplitudes was significantly lower in CAA compared to controls (p < 0.001). White matter hyperintensity (WMH) volumes and number of cerebral microbleeds, both presumed to reflect CAA-mediated vascular injury, increased over time in CAA (p = 0.007 and p = 0.001, respectively). Longitudinal increases in WMH (rs = 0.04, p = 0.86) or cerebral microbleeds (rs = − 0.18, p = 0.45) were not associated with the longitudinal decrease in BOLD amplitudes.