Blood Oxygen Level-dependent Response Research Articles

E.3 fMRI correlates of symptom-specific improvement in STN deep brain stimulation

Background: Subthalamic nucleus (STN) deep brain stimulation (DBS) improves the cardinal symptoms of Parkinson’s disease (PD). However, the therapeutic mechanisms are incompletely understood. By leveraging patient-specific brain responses to DBS using functional magnetic resonance imaging (fMRI) acquired during stimulation, we identify and validate symptom-specific networks associated with clinical improvement. Methods: Forty PD patients with STN-DBS were enrolled for fMRI using a 30-sec DBS-ON/OFF cycling paradigm. The four cardinal motor outcomes of PD were chosen a priori and measured using the Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale, part III (MDS-UPDRSIII): axial instability, tremor, rigidity, bradykinesia. Stimulation-dependent changes in blood oxygen level-dependent (BOLD) signal were correlated with each symptom. Results: The relationship between BOLD response and outcomes revealed significant networks of clinical response (p<0.001). Using BOLD responses from the network hubs, each symptom-specific model was significantly predictive of actual improvement: axial instability (R2=0.38, p=0.000026), bradykinesia (R2=0.29, p=0.00033), rigidity (R2=0.40, p=0.000013), tremor (R2=0.26, p=0.00073). Conclusions: Using patient-specific imaging, we provide evidence of an association between DBS-evoked fMRI response and individual symptom improvement. Brain networks associated with clinical improvement were different depending on the PD symptom examined, suggesting the presence of symptom-specific networks of efficacy which may allow personalization of DBS therapy.

Mapping interictal discharges using intracranial EEG-fMRI to predict postsurgical outcomes.

Various subjective and objective methods have been proposed to identify which interictal epileptiform discharge (IED)-related EEG-fMRI results are more likely to delineate seizure generating tissue in patients with drug-resistant focal epilepsy for the purposes of surgical planning. In this intracranial EEG-fMRI study, we evaluated the utility of these methods to localize clinically relevant regions pre-operatively and compared the extent of resection of these areas to post-operative outcome. Seventy patients admitted for intracranial video-EEG monitoring were recruited for a simultaneous intracranial EEG-fMRI study. For all analyses of blood oxygen level-dependent responses associated with IEDs, an experienced epileptologist identified the most Clinically Relevant brain activation cluster using available clinical information. The Maximum cluster (the cluster with the highest z-score) was also identified for all analyses and assigned to one of three confidence levels (low, medium, or high) based on the difference of the peak z-scores between the Maximum and Second Maximum cluster (the cluster with the second highest peak z-value). The distance was measured and compared between the peak voxel of the aforementioned clusters and the electrode contacts where the interictal discharge and seizure onset were recorded. In patients who subsequently underwent epilepsy surgery, the spatial concordance between the aforementioned clusters and the area of resection was determined and compared to post-operative outcome. We evaluated 106 different IEDs in 70 patients. Both subjective (identification of the Clinically Relevant cluster) and objective (Maximum cluster much more significant than the second maximum cluster) methods of culling non-localizing EEG-fMRI activation maps increased the spatial concordance between these clusters and the corresponding IED or seizure onset zone contacts. However, only the objective methods of identifying medium and high confidence maps resulted in a significant association between resection of the peak voxel of the Maximum cluster and post-operative outcome. Resection of this area was associated with good post-operative outcomes but was not sufficient for seizure freedom. On the other hand, we found that failure to resect the medium and high confidence Maximum clusters was associated with a poor post-surgical outcome (negative predictive value = 1.0, sensitivity = 1.0). Objective methods to identify higher confidence EEG-fMRI results are needed to localize areas necessary for good post-operative outcomes. However, resection of the peak voxel within higher confidence Maximum clusters is not sufficient for good outcomes. Conversely, failure to resect the peak voxel in these clusters is associated with a poor post-surgical outcome.

P157 Neurocognitive insights: functional magnetic resonance imaging of spatial working memory and sustained attention in people with systemic lupus erythematous

Abstract Background/Aims Cognitive impairment (CI) is common in people with systemic lupus erythematosus (pwSLE). Treatment options are limited and the effects upon the brain is unclear. Differences in brain structure seen in SLE do not always associate with CI, however significant associations have been found with functional magnetic resonance imaging (fMRI). Using fMRI, this study aims to further explore potential compensatory brain mechanisms used in SLE that help with cognitive function. Methods Participants were recruited into one of two groups;pwSLE (meeting EULAR/ACR criteria) or healthy controls(HC). Demographic, clinical and psychiatric data and patient reported outcome measures were collected.Cognitive function was assessed using the ACR Neuropsychological Battery. Brain scans included two structural and two fMRI scans done during stage 1 and 2 of a cognitive task. Stage 1 of the task had an encoding, retention and working memory (WM) component. Stage 2 of the task examined long-term memory. Differences between task performances were examined using t-tests. The fMRI data was modelled using SPM12 to look for differences in blood-oxygen-level-dependent (BOLD) brain responses between the study groups during the different stages/components of the task. Results To-date 37 pwSLE and 10 HCs have been recruited. The median ages were 36 (HC) and 40 (pwSLE) years. From the pwSLE group the average disease duration was 15 years, the average SLEDAI-2K score was 5 and percentages of those on antimalarials, corticosteroids, and immunosuppressants and biologics were 66%, 32%, and 54%, respectively. There were no differences on task performance between the two groups. Greater BOLD responses were seen in the HC compared to the pwSLE group during stage 1 encoding and WM phases as well as during stage 2 (long-term memory). pwSLE had less attenuated BOLD signals during the stage 1 retention phase compared to HCs (Table 1). Conclusion We found altered brain responses to our cognitive task between pwSLE and HCs. Predominantly the HC group had greater BOLD responses in cognitive regions during the task compared to the pwSLE group. However, we did not find any difference between the two groups in regards to cognitive performance. This study is still ongoing and additional results are expected. Disclosure M. Barraclough: None. M. McCowen: None. S. McKie: None. A. Kafkas: None. B. Parker: None. J. Diaz-Martinez: None. A. Knight: None. K. Bingham: None. M. Li: None. J. Su: None. M. Kakvan: None. C. Munoz Grajales: None. M. Tartaglia: None. L. Ruttan: None. J. Wither: None. D. Bonilla: None. N. Anderson: None. D. Montaldi: None. R. Elliott: None. P. Katz: None. D. Beaton: None. R. Green: None. I. Bruce: None. Z. Touma: None.

No replication of direct neuronal activity-related (DIANA) fMRI in anesthetized mice.

Direct imaging of neuronal activity (DIANA) by functional magnetic resonance imaging (fMRI) could be a revolutionary approach for advancing systems neuroscience research. To independently replicate this observation, we performed fMRI experiments in anesthetized mice. The blood oxygenation level-dependent (BOLD) response to whisker stimulation was reliably detected in the primary barrel cortex before and after DIANA experiments; however, no DIANA-like fMRI peak was observed in individual animals' data with the 50 to 300 trials. Extensively averaged data involving 1050 trials in six mice showed a flat baseline and no detectable neuronal activity-like fMRI peak. However, spurious, nonreplicable peaks were found when using a small number of trials, and artifactual peaks were detected when some outlier-like trials were excluded. Further, no detectable DIANA peak was observed in the BOLD-responding thalamus from the selected trials with the neuronal activity-like reference function in the barrel cortex. Thus, we were unable to replicate the previously reported results without data preselection.

Brain atrophy, reduced cerebral perfusion, arterial stiffening, and wall thickening with aging coincide with stimulus-specific changes in fMRI-BOLD responses.

The aim of this study was to investigate how aging affects blood flow and structure of the brain. It was hypothesized older individuals would have lower gray matter volume (GMV), resting cerebral blood flow (CBF0), and depressed responses to isometabolic and neurometabolic stimuli. In addition, increased carotid-femoral pulse-wave velocity (PWV), carotid intima-media thickness (IMT), and decreased brachial flow-mediated dilation (FMD) would be associated with lower CBF0, cerebrovascular reactivity (CVR), and GMV. Brain scans (magnetic resonance imaging) and cardiovascular examinations were conducted in young (age = 24 ± 3 yr, range = 22-28 yr; n = 13) and old (age = 71 ± 4 yr; range = 67-82 yr, n = 14) participants, and CBF0, CVR [isometabolic % blood oxygen level-dependent (BOLD) in response to a breath hold (BH)], brain activation patterns during a working memory task (neurometabolic %BOLD response to N-back trial), GMV, PWV, IMT, and FMD were measured. CBF0 and to a lesser extent CVRBH were lower in the old group (P ≤ 0.050); however, the increase in the %BOLD response to the memory task was not blunted (P ≥ 0.2867). Age-related differential activation patterns during the working memory task were characterized by disinhibition of the default mode network in the old group (P < 0.0001). Linear regression analyses revealed PWV, and IMT were negatively correlated with CBF0, CVRBH, and GMV across age groups, but within the old group alone only the relationships between PWV-CVRBH and IMT-GMV remained significant (P ≤ 0.0183). These findings suggest the impacts of age on cerebral %BOLD responses are stimulus specific, brain aging involves alterations in cerebrovascular and possibly neurocognitive control, and arterial stiffening and wall thickening may serve a role in cerebrovascular aging.NEW & NOTEWORTHY Cerebral perfusion was lower in old versus young adults. %Blood oxygen level-dependent (BOLD) responses to an isometabolic stimulus and gray matter volume were decreased in old versus young adults and associated with arterial stiffening and wall thickening. The increased %BOLD response to a neurometabolic stimulus appeared unaffected by age; however, the old group displayed disinhibition of the default mode network during the stimulus. Thus, age-related alterations in cerebral %BOLD responses were stimulus specific and related to arterial remodeling.

Thermal stimulus task fMRI in the cervical spinal cord at 7 Tesla.

Although functional magnetic resonance imaging (fMRI) is widely applied in the brain, fMRI of the spinal cord is more technically demanding. Proximity to the vertebral column and lungs results in strong spatial inhomogeneity and temporal fluctuations in B0 . Increasing field strength enables higher spatial resolution and improved sensitivity to blood oxygenation level-dependent (BOLD) signal, but amplifies the effects of B0 inhomogeneity. In this work, we present the first task fMRI in the spinal cord at 7 T. Further, we compare the performance of single-shot and multi-shot 2D echo-planar imaging (EPI) protocols, which differ in sensitivity to spatial and temporal B0 inhomogeneity. The cervical spinal cords of 11 healthy volunteers were scanned at 7 T using single-shot 2D EPI at 0.75 mm in-plane resolution and multi-shot 2D EPI at 0.75 and 0.6 mm in-plane resolutions. All protocols used 3 mm slice thickness. For each protocol, the BOLD response to 13 10-s noxious thermal stimuli applied to the right thumb was acquired in a 10-min fMRI run. Image quality, temporal signal to noise ratio (SNR), and BOLD activation (percent signal change and z-stat) at both individual- and group-level were evaluated between the protocols. Temporal SNR was highest in single-shot and multi-shot 0.75 mm protocols. In group-level analyses, activation clusters appeared in all protocols in the ipsilateral dorsal quadrant at the expected C6 neurological level. In individual-level analyses, activation clusters at the expected level were detected in some, but not all subjects and protocols. Single-shot 0.75 mm generally produced the highest mean z-statistic, while multi-shot 0.60 mm produced the best-localized activation clusters and the least geometric distortion. Larger than expected within-subject segmental variation of BOLD activation along the cord was observed. Group-level sensory task fMRI of the cervical spinal cord is feasible at 7 T with single-shot or multi-shot EPI. The best choice of protocol will likely depend on the relative importance of sensitivity to activation versus spatial localization of activation for a given experiment. PRACTITIONER POINTS: First stimulus task fMRI results in the spinal cord at 7 T. Single-shot 0.75 mm 2D EPI produced the highest mean z-statistic. Multi-shot 0.60 mm 2D EPI provided the best-localized activation and least distortion.

Heartbeat-evoked neural response abnormalities in generalized anxiety disorder during peripheral adrenergic stimulation.

Hyperarousal symptoms in generalized anxiety disorder (GAD) are often incongruent with the observed physiological state, suggesting that abnormal processing of interoceptive signals is a characteristic feature of the disorder. To examine the neural mechanisms underlying interoceptive dysfunction in GAD, we evaluated whether adrenergic modulation of cardiovascular signaling differentially affects the heartbeat-evoked potential (HEP), an electrophysiological marker of cardiac interoception, during concurrent electroencephalogram and functional magnetic resonance imaging (EEG-fMRI) scanning. Intravenous infusions of the peripheral adrenergic agonist isoproterenol (0.5 and 2.0 micrograms, μg) were administered in a randomized, double-blinded and placebo-controlled fashion to dynamically perturb the cardiovascular system while recording the associated EEG-fMRI responses. During the 0.5 μg isoproterenol infusion, the GAD group (n = 24) exhibited significantly larger changes in HEP amplitude in an opposite direction than the healthy comparison (HC) group (n = 24). In addition, the GAD group showed significantly larger absolute HEP amplitudes than theHC groupduring saline infusions, when cardiovascular tone did not increase. No significant group differences in HEP amplitude were identified during the 2.0 μg isoproterenol infusion. Using analyzable blood oxygenation level-dependent fMRI data from participants with concurrent EEG-fMRI data (21 GAD and 21 HC), we found that the aforementioned HEP effects were uncorrelated with fMRI signals in the insula, ventromedial prefrontal cortex, dorsal anterior cingulate cortex, amygdala, and somatosensory cortex, brain regions implicated in cardiac signal processing in prior fMRI studies. These findings provide additional evidence of dysfunctional cardiac interoception in GAD and identify neural processes at the electrophysiological level that may be independent from blood oxygen level-dependent responses during peripheral adrenergic stimulation.

Potential for a cerebellar role in moderate-late preterm associated behavioural disorders.

Preterm birth is known to cause impaired cerebellar development, and this is associated with the development of neurobehavioral disorders. This review aims to identify the mechanisms through which preterm birth impairs cerebellar development and consequently, increases the risk of developing neurobehavioral disorders. The severity of these disorders is directly related to the degree of prematurity, but it is also evident that even late preterm births are at significantly increased risk of developing serious neurobehavioral disorders. Preterm birth is associated with hypoxic events and increased glutamatergic tone within the neonatal brain which contribute to excitotoxic damage. The cerebellum is a dense glutamatergic region which undergoes relatively late neurodevelopment up to and beyond birth. Evidence indicates that the cerebellum forms reciprocal connections to regions important in behaviour regulation such as the limbic system and frontal cortex. Studies using fMRI (functional magnetic resonance Imaging), BOLD (blood oxygen level dependent) response and morphology studies in humans show the cerebellum is often involved in disorders such as attention deficit hyperactivity disorder (ADHD) and anxiety. The vulnerability of the cerebellum to preterm birth insult and its connections to behaviour associated brain regions implicates it in the development of neurobehavioral disorders. Protection against preterm associated insults on the cerebellum may provide a novel avenue through which ADHD and anxiety can be reduced in children born preterm.

Simultaneous fMRI and metabolic MRS of hyperpolarized [1-13C]pyruvate during nicotine stimulus in rat.

Functional MRI (fMRI) and MRS (fMRS) can be used to noninvasively map cerebral activation and metabolism. Recently, hyperpolarized 13C spectroscopy and metabolic imaging have provided an alternative approach to assess metabolism. In this study, we combined 1H fMRI and hyperpolarized [1-13C]pyruvate MRS to compare cerebral blood oxygenation level-dependent (BOLD) response and real-time cerebral metabolism, as assessed with lactate and bicarbonate labelling, during nicotine stimulation. Simultaneous 1H fMRI (multislice gradient echo echo-planar imaging) and 13C spectroscopic (single slice pulse-acquire) data were collected in urethane-anaesthetized female Sprague-Dawley rats (n= 12) at 9.4 T. Animals received an intravenous (i.v.) injection of either nicotine (stimulus; 88 μg/kg, n= 7, or 300 μg/kg, n= 5) or 0.9% saline (matching volume), followed by hyperpolarized [1-13C]pyruvate injection 60 s later. Three hours later, a second injection was administered: the animals that had previously received saline were injected with nicotine and vice versa, both followed by another hyperpolarized [1-13C]pyruvate i.v. injection 60 s later. The low-dose (88 μg/kg) nicotine injection led to a 12% ± 4% (n= 7, t-test, p~ 0.0006 (t-value -5.8, degrees of freedom 6), Wilcoxon p~ 0.0078 (test statistic 0)) increase in BOLD signal. At the same time, an increase in 13C-bicarbonate signal was seen in four out of six animals. Bicarbonate-to-total carbon ratios were 0.010 ± 0.004 and 0.018 ± 0.010 (n= 6, t-test, p~ 0.03 (t-value -2.3, degrees of freedom 5), Wilcoxon p~ 0.08 (test statistic 3)) for saline and nicotine experiments, respectively. No increase in the lactate signal was seen; lactate-to-total carbon was 0.16 ± 0.02 after both injections. The high (300 μg/kg) nicotine dose (n= 5) caused highly variable BOLD and metabolic responses, possibly due to the apparent respiratory distress. Simultaneous detection of 1H fMRI and hyperpolarized 13C-MRS is feasible. A comparison of metabolic response between control and stimulated states showed differences in bicarbonate signal, implying that the hyperpolarization technique could offer complimentary information on brain activation.

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.

Neurovascular coupling reflex from contralateral stimulation: System setup

Aims/Purpose: Neurovascular coupling (NVC) is the blood flow modulation in response to stimuli and has been extensively studied in the brain. Concerning the human retina, this behaviour has been only measured in the ipsilateral eye, where stimuli and observed effects involve the same eye. This work aims to set up the hardware to assess NVC in the contralateral eye and demonstrate its feasibility in edifying human retina‐retina or cortico‐retinal connections.Methods: Adaptive optics (AO) is a cutting‐edge technology in retinal fundus imaging, offering exceptional spatial resolution. The NVC effect was successfully assessed using the RTX1, an AO retinal camera capable of ipsilateral stimulation. The possible effects of contralateral stimulation can be readily assessed by providing RTX1 with an external flickering device. Furthermore, connecting the thread between previous fMRI results and photic stimulation in the ipsi‐ and contralateral retina can offer valuable information on uncharted interocular or brain‐retina neural pathways and lead to cost‐effective and non‐invasive biomarkers for neurodegenerative diseases or early brain vasculature impairment diagnosis.Results: Even though further optimization of flicker‐related parameters is necessary to investigate the contralateral NVC response, preliminary tests showed the successful integration of a fully operational contralateral stimulation prototype with the RTX1. The entire procedure has been documented, and all components have been thoroughly evaluated.Conclusions: These preliminary assessments precede a clinical study involving patients with type 1 Diabetes Mellitus and a control group of healthy individuals. It follows previous fMRI studies that showed impaired NVC in type 2 diabetic patients by measuring the BOLD (Blood Oxygen Level‐Dependent) response using block and event‐related optical stimuli. A comparative analysis of the findings aims to demonstrate the potential role of neurovascular uncoupling in the early pathogenesis of diabetic retinopathy.

AUTONOMIC ACTIVITY AND THE AGING BRAIN

Abstract Aging affects both autonomic activity and the brain regions that help modulate autonomic activity. In this symposium, we present new findings on how the relationships between autonomic activity and the brain change in aging. In addition, we demonstrate that modulating autonomic activity can affect the aging brain and emotional and cognitive functions controlled by the brain. Kathy Liu will present research from over 600 participants showing that, unlike younger adults who show the expected positive relationship between heart rate variability (HRV) and brain and behavioral indicators of emotion regulation, older adults showed a negative relationship between HRV and emotion regulation. Julian Thayer will present findings on how blood pressure and total peripheral resistance relate to brain structure. Richard Song will present functional MRI data revealing that the older brain shows less blood oxygen level dependent (BOLD) response to physiological fluctuations than younger brains. Jungwon Min will present findings that random assignment to daily biofeedback to either increase or decrease heart rate oscillations had a large effect on plasma amyloid-β. Mara Mather will present a new theoretical model positing that older brains attempt to compensate for hyperactive peripheral sympathetic activity, and that this ventromedial prefrontal compensatory activity leads to the biases in attention and memory known as the age-related positivity effect. Together, the empirical findings and theoretical perspectives presented in this symposium indicate that the autonomic system exerts important influences over the aging brain and that this provides a significant opportunity for intervening to improve brain health.

Locus coeruleus hyperactivity in middle age may be associated with better cognitive performance

AbstractBackgroundMeasuring the health of the locus coeruleus (LC), the brainstem site of the first cellular damage in Alzheimer’s Disease (AD) pathogenesis, is of particular interest for early diagnosis. In both rodents and humans (Elman 2017; Kelberman 2023; Malatt 2022; Weinshenker 2008), increased tonic firing rates have been noted in middle age. This occurs prior to the hypoactivity and reduced functional and structural connectivity associated with cognitive aging (Jacobs 2015; Kelberman 2022; Langley 2022; Prokopiou 2022) . Understanding the mechanism or function behind LC hyperactivity in middle age may be key to identifying individuals on pathological aging trajectories.MethodParticipants (29 younger, 18 middle‐aged, 24 older) performed a dual attention task in the scanner with multi‐echo fMRI and concurrent pupillometry. Cognition was assessed with NIH Toolbox Cognitive Battery (Fluid Composite) and sorted into high (&gt;50th percentile) or low (&lt;50th) categories. Age groupings were determined by a pupillary behavior data analysis.Results Pupil (Fig. 1): using a linear mixed effects model to predict the dynamic range‐normalized pupillary response area under the curve (AUC) from age group and trial type, there was a significant effect of age and significant age*trial type interactions. Middle‐aged adults had larger responses than other groups. Using a model to predict AUC from cognitive category and trial type, there was a significant interaction between cognitive category and trial type, with the high cognitive group having larger target and distractor responses. Blood‐Oxygen‐Level‐Dependent (BOLD) (Fig. 2): using a linear mixed effects model to predict LC BOLD response from age group and trial type, there was no significant effect of age but a significant age*trial type interaction. Middle‐aged adults had larger distractor responses and older adults had smaller target responses. Using a model to predict BOLD response from cognitive category and trial type, there was no significant effect of category, but there was a significant interaction between category and trial type, with the high cognitive group having larger target and distractor responses.ConclusionsElevated LC BOLD and pupillary responses to target trials in middle age are associated with better cognitive performance. LC hyperactivity may be adaptive in middle age.

Poster Session I: Binocular facilitation of the BOLD response to melanopsin stimulation in the suprachiasmatic nucleus.

In a recent analysis of archival data, Spitschan and Cajochen (2019) identify what appears to be substantial binocular facilitation of melatonin suppression due to melanopic light stimulation. This putative effect likely originates in the melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) which project directly to the suprachiasmatic nucleus (SCN) of the hypothalamus. We asked whether we could measure a direct physiological correlate of this binocular facilitation using a binocular, MRI-compatible, 10-primary spectral stimulation device. We present preliminary findings from a functional magnetic resonance imaging (fMRI) study designed to explore the blood oxygen level dependent (BOLD) response to monocular and binocular melanopic light stimulation. The study used a 30 s on/off design with three 'ocularity' conditions (binocular-low, monocular-high, binocular-high) and two classes of targeted photoreceptors (melanopsin and LMS cones). Throughout each scan, subjects (N=18) also responded to brief, cone-directed sinusoidal modulations of varying intensity. We report that binocular vs. monocular melanopsin stimulation induced significant BOLD activation in SCN but that this effect was not seen for cone-directed stimulation. This is consistent with the binocular facilitation effect described by Spitschan and Cajochen (2019) and provides the first direct evidence of melanopsin-driven activation and binocular facilitation in human subcortical nuclei.

Neurovascular Coupling in Hypertensive COVID‐19 Survivors Medicated With Different Classes of RAS Inhibitors: A Pilot Study

AbstractBackgroundHypertension poses an increased risk of Alzheimer’s disease (AD). Coronavirus disease 2019 (COVID‐19) may exacerbate this risk by affecting the Renin‐Angiotensin system (RAS), which contributes to the regulation of neurovascular coupling (NVC). NVC is a mechanism that optimizes cerebral blood flow (CBF) to meet the metabolic and waste‐removal needs of the brain. Disrupted NVC may predispose individuals to AD through hypoxia‐related protein changes and suboptimal protein‐waste removal from the brain. Several studies reported reduced CBF in long‐haul COVID‐19 patients. Among antihypertensive medicines that target the RAS, angiotensin receptor blockers (ARBs), but not angiotensin‐converting enzyme inhibitors (ACEIs), were previously found to regulate CBF. Therefore, we hypothesized that, if taken during and after a COVID‐19 episode, ARBs rather than ACEIs would be protective against long‐term CBF dysregulation.MethodWe quantified NVC through a novel analysis paradigm that takes advantage of simultaneous resting‐state electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). We obtained scans from older adult participants (aged 55‐80), including healthy controls and hypertensive COVID‐19 survivors medicated with ARBs or ACEIs during their COVID‐19 infection (occurring 3‐27 months before scanning). Hidden Markov modeling on source‐localized EEG was used to detect transient electrophysiological activity in distinct neural networks. A rapid event‐related fMRI analysis deconvolved the blood oxygenation level‐dependent (BOLD) changes evoked by the network‐specific electrophysiological activations. NVC was measured as the slope of vascular BOLD changes over the time‐locked electrophysiological neural changes.ResultIn this pilot study, the default mode network (DMN) showed differences in NVC between the hypertensive COVID‐19 survivors and the healthy control group. Crucially, the ARB‐medicated subgroup, like the control group, showed the BOLD response in the DMN regions time‐locked to the DMN electrophysiological activations; NVC differences between the ARB‐medicated and control groups did not reach significance. In contrast, the ACEI‐medicated subgroup showed a reduced NVC in the DMN relative to the control group.ConclusionThe DMN, which is linked to memory dysfunction in AD, may be vulnerable to NVC disruptions, given its high metabolic demands. Hypertension management with ARBs may reduce COVID‐19’s effects on cerebrovascular regulation, preventing ischemic stroke, vascular dementia, and AD. Results replication is warranted.

Effects of a single dose of amisulpride on functional brain changes during reward- and motivation-related processing using task-based fMRI in healthy subjects and patients with major depressive disorder — study protocol for a randomized clinical trial

BackgroundAnhedonia and other deficits in reward- and motivation-related processing in psychiatric patients, including patients with major depressive disorder (MDD), represent a high unmet medical need. Neurobiologically, these deficits in MDD patients are mainly associated with low dopamine function in a frontostriatal network. In this study, alterations in brain activation changes during reward processing and at rest in MDD patients compared with healthy subjects are explored and the effects of a single low dose of the dopamine D2 receptor antagonist amisulpride are investigated.MethodsThis is a randomized, controlled, double-blind, single-dose, single-center parallel-group clinical trial to assess the effects of a single dose of amisulpride (100 mg) on blood-oxygenation-level-dependent (BOLD) responses during reward- and motivation-related processing in healthy subjects (n = 60) and MDD patients (n = 60). Using functional magnetic resonance imaging (fMRI), BOLD responses are assessed during the monetary incentive delay (MID) task (primary outcome). Exploratory outcomes include BOLD responses and behavioral measures during the MID task, instrumental learning task, effort-based decision-making task, social incentive delay task, and probabilistic reward task as well as changes in resting state functional connectivity and cerebral blood flow.DiscussionThis study broadly covers all aspects of reward- and motivation-related processing as categorized by the National Institute of Mental Health Research Domain Criteria and is thereby an important step towards precision psychiatry. Results regarding the immediate effects of a dopaminergic drug on deficits in reward- and motivation-related processing not only have the potential to significantly broaden our understanding of underlying neurobiological processes but might eventually also pave the way for new treatment options.Trial registrationClinicalTrials.gov NCT05347199. April 12, 2022.

Neonatal neural responses to novelty related to behavioral inhibition at 1 year.

Behavioral inhibition (BI), an early-life temperament characterized by vigilant responses to novelty, is a risk factor for anxiety disorders. In this study, we investigated whether differences in neonatal brain responses to infrequent auditory stimuli relate to children's BI at 1 year of age. Using functional magnetic resonance imaging (fMRI), we collected blood-oxygen-level-dependent (BOLD) data from N = 45 full-term, sleeping neonates during an adapted auditory oddball paradigm and measured BI from n = 27 of these children 1 year later using an observational assessment. Whole-brain analyses corrected for multiple comparisons identified 46 neonatal brain regions producing novelty-evoked BOLD responses associated with children's BI scores at 1 year of age. More than half of these regions (n = 24, 52%) were in prefrontal cortex, falling primarily within regions of the default mode or frontoparietal networks or in ventromedial/orbitofrontal regions without network assignments. Hierarchical clustering of the regions based on their patterns of association with BI resulted in two groups with distinct anatomical, network, and response-timing profiles. The first group, located primarily in subcortical and temporal regions, tended to produce larger early oddball responses among infants with lower subsequent BI. The second group, located primarily in prefrontal cortex, produced larger early oddball responses among infants with higher subsequent BI. These results provide preliminary insights into brain regions engaged by novelty in infants that may relate to later BI. The findings may inform understanding of anxiety disorders and guide future research. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Abstract 15900: Probing Mitochondrial Dysfunction in Mouse Hearts With Doxorubicin-Induced Cardiotoxicity Using Ungated 4D Oxy-Wavelet MRI

Introduction: Despite advances in cancer therapy greatly improving patient survival, more than two-thirds of cancer survivors will still face serious life-threatening cardiomyopathy caused by anti-cancer anthracyclines. Doxorubicin (Dox), a well-known, well studied anthracycline, is a major cause for long-term morbidity and mortality among cancer survivors. Pertinent to this issue is the lack of non-invasive imaging tools that can detect DOX induced cardiomyopathy before irreversible tissue damage is done. Current research of cellular mechanisms underlying DOX-induced cardiotoxicity has shown that mitochondrial dysfunction are central to this cardiomyopathy. Hypothesis: We hypothesize that this mitochondrial dysfunction precedes clinical changes in cardiac strain and left-ventricle ejection fraction. Methods: To probe mitochondrial function non-invasively, we use motion-and-time resolved 4D functional MRI, coined 4D Oxy-Wavelet. Our methodology can capture dynamic changes in the blood oxygenation level dependent (BOLD) signal with high spatiotemporal resolution. Our cyclic hypoxia challenge leverages the need for in-tact mitochondrial function to maintain homeostatic oxygenation during hypoxia. We combine our 4D-fMRI methodology with a cyclic hypoxia challenge to stress-test the mitochondria in a mouse model of DOX-induced cardiotoxicity. We use a novel time-frequency analysis of the event-driven BOLD response to automate the detection of mitochondrial dysfunction in-vivo. Results: C57BL6/J were given Dox over the course of one week. 4D oxy-wavelet MRI was performed at baseline, day 1, 3, 4, and 7 to evaluate the ability to rapidly detect acute DOX induced cardiotoxicity. We found that as early as day one post exposure, mice exhibited a passive response to the hypoxia challenge, representing an inability to maintain homeostatic oxygen and underlying mitochondria dysfunction, that was maintained through this acute period.

Electroencephalography-functional magnetic resonance imaging for clinical evaluation in focal epilepsy.

We aimed to evaluate the contribution of simultaneous recording of electroencephalography-functional magnetic resonance imaging (EEG-fMRI) in the diagnosis of epilepsy syndrome, localization of the epileptogenic zone (EZ), and decision-making regarding surgical treatment. We performed a retrospective study to evaluate patients with focal epilepsy who underwent EEG-fMRI. Two evaluators assessed epilepsy syndrome, presumed focus, and surgical candidacy and defined confidence levels. They assessed these clinical characteristics first without EEG-fMRI and then including EEG-fMRI to assess how the results of EEG-fMRI changed the evaluations. We also determined how the clinical evaluation was affected by the concordance level between the blood oxygen level-dependent (BOLD) response and the presumed focus location, and by the confidence level of the BOLD response itself based on the t-value of the primary and secondary clusters. Fifty-one scans from 48 patients were included. The BOLD map affected 66.7% of the evaluations by altering evaluation items (epilepsy syndrome, presumed focus, or surgical candidacy) or their confidence levels. EEG-fMRI results increased the confidence levels of epilepsy syndrome, presumed focus, or surgical candidacy in 47.1% of patients but reduced clinical confidence in these features in 11.8%. More specifically, the confidence levels increased for epilepsy syndrome in 28.5%, identification of presumed focus in 33.9%, and determination of surgical candidacy in 29.4%. The BOLD signal confidence level, whether high or low, did not influence these clinical factors. Previous studies have emphasized the utility of EEG-fMRI for the localization of the epileptogenic zone. This study demonstrated the potential of EEG-fMRI to influence clinical confidence when determining epilepsy syndrome, the presumed epileptic focus, and surgical candidacy.

Functional MRI activation of the nucleus tractus solitarius after taste stimuli at ultra-high field: a proof-of-concept single-subject study

Using ultra-high field (7 Tesla) functional MRI (fMRI), we conducted the first in-vivo functional neuroimaging study of the normal human brainstem specifically designed to examine neural signals in the Nucleus Tractus Solitarius (NTS) in response to all basic taste stimuli. NTS represents the first relay station along the mammalian taste processing pathway which originates at the taste buds in the oral cavity and passes through the thalamus before reaching the primary taste cortex in the brain. In our proof-of-concept study, we acquired data from one adult volunteer using fMRI at 1.2 mm isotropic resolution and performed a univariate general linear model analysis. During fMRI acquisition, three shuffled injections of sweet, bitter, salty, sour, and umami solutions were administered following an event-related design. We observed a statistically significant blood oxygen level-dependent (BOLD) response in the anatomically predicted location of the NTS for all five basic tastes. The results of this study appear statistically robust, even though they were obtained from a single volunteer. The information derived from a similar experimental strategy may inspire novel research aimed at clarifying important details of central nervous system involvement in eating disorders, at designing and monitoring tailored therapeutic strategies.