Estimating the synaptic density deficit in Alzheimer's disease using multi-contrast CEST imaging.

In vivo noninvasive imaging of neurometabolites is crucial to improve our understanding of the underlying pathophysiological mechanism in neurodegenerative diseases. Abnormal changes in synaptic organization leading to synaptic degradation and neuronal loss is considered as one of the primary factors driving Alzheimer's disease pathology. Magnetic resonance based molecular imaging techniques such as chemical exchange saturation transfer (CEST) and magnetic resonance spectroscopy (MRS) can provide neurometabolite specific information which may relate to underlying pathological and compensatory mechanisms. In this study, CEST and short echo time single voxel MRS was performed to evaluate the sensitivity of cerebral metabolites to beta-amyloid (Aß) induced synaptic deficit in the hippocampus of a mouse model of Alzheimer's disease. The CEST based spectra (Z-spectra) were acquired on a 9.4 Tesla small animal MR imaging system with two radiofrequency (RF) saturation amplitudes (1.47 µT and 5.9 µT) to obtain creatine-weighted and glutamate-weighted CEST contrasts, respectively. Multi-pool Lorentzian fitting and quantitative T1 longitudinal relaxation maps were used to obtain metabolic specific apparent exchange-dependent relaxation (AREX) maps. Short echo time (TE = 12 ms) single voxel MRS was acquired to quantify multiple neurometabolites from the right hippocampus region. AREX contrasts and MRS based metabolite concentration levels were examined in the ARTE10 animal model for Alzheimer's disease and their wild type (WT) littermate counterparts (age = 10 months). Using MRS voxel as a region of interest, group-wise analysis showed significant reduction in Glu-AREX and Cr-AREX in ARTE10, compared to WT animals. The MRS based results in the ARTE10 mice showed significant decrease in glutamate (Glu) and glutamate-total creatine (Glu/tCr) ratio, compared to WT animals. The MRS results also showed significant increase in total creatine (tCr), phosphocreatine (PCr) and glutathione (GSH) concentration levels in ARTE10, compared to WT animals. In the same ROI, Glu-AREX and Cr-AREX demonstrated positive associations with Glu/tCr ratio. These results indicate the involvement of neurotransmitter metabolites and energy metabolism in Aß-mediated synaptic degradation in the hippocampus region. The study also highlights the feasibility of CEST and MRS to identify and track multiple competing and compensatory mechanisms involved in heterogeneous pathophysiology of Alzheimer's disease in vivo.

Altered corollary discharge in the auditory cortex could reflect louder inner voice experience in patients with verbal hallucinations, a pilot fMRI study.

INTRODUCTION: Wide range of evidence associates auditory verbal hallucinations (AVH) with frontotemporal corollary discharge deficit. AVH likely reflect altered experiences of the inner voice and are phenomenologically diverse. The aspects of hallucinations (and related inner voice experiences) that could be explained by this deficit remain unclear. To address this important subject, we examined the temporal cortex activity during two tasks with and without corollary discharge. METHODS: We carried out an event-related BOLD fMRI study to examine temporal cortex activity in seven patients and eight healthy controls during two tasks with and without corollary discharge: reading aloud and hearing, respectively. Data were denoised by removing independent components related to head movement and subsequently processed using finite impulse response basis function to address hemodynamic response variations. To mitigate the small sample size, final analyses were carried out using permutation-based analysis of variance. RESULTS: There was a significant group interaction in the Read relative to Hear condition during the early post-stimulus stage in the left Heschl's Gyrus (p<0.01, corrected for multiple comparisons, at peak voxel [-72,53,41]). This effect was driven by a higher activity in the Read relative to the Hear condition in the same area in the patients (p<0.02, corrected). CONCLUSIONS: Our results are consistent with prior literature indicating abnormal frontotemporal disconnection in participants with hallucinations. The functional repercussions of this deficit were limited to the primary auditory cortex in early post-stimulus stage, which suggests louder experience of the inner voice in patients and could account for the loudness of their hallucinations.

High-intensity sweet taste as a predictor of subjective alcohol responses to the ascending limb of an intravenous alcohol prime: an fMRI study.

High-intensity sweet-liking has been linked to alcohol use disorder (AUD) risk. However, the neural underpinning of this association is poorly understood. To find a biomarker predictive of AUD, 140 participants (social and heavy drinkers, ages 21-26) underwent functional magnetic resonance imaging (fMRI) during a monetary incentive delay (MID) task and stimulation with high (SucroseHigh)- and low-concentration sucrose, as well as viscosity-matched water. On another day after imaging, and just before free-access intravenous alcohol self-administration, participants experienced a 30 mg% alcohol prime (10 min ascent) using the Computerized Alcohol Infusion System. Principal component analysis (PCA) of subjective responses (SR) to the prime's ascending limb generated enjoyable (SRenjoy) and sedative (SRsed) intoxication components. Another PCA created one component reflective of self-administered alcohol exposure (AE) over 90 min. Component loadings were entered as regressors in a voxel-wise general linear fMRI model, with reward type as a fixed factor. By design, peak prime breath alcohol concentration was similar across participants (29 ± 3.4 mg%). SRenjoy on the prime's ascending limb correlated positively with [SucroseHigh > Water] in the supplementary motor area and right dorsal anterior insula, implicating the salience network. Neither SR component correlated with the brain's response to MID. AE was unrelated to brain reward activation. While these findings do not support a relationship between alcohol self-administration and (1) subjective liking of or (2) regional brain response to an intensely sweet taste, they show that alcohol's enjoyable intoxicating effects on the rising limb correspond with anterior insular and supplementary motor area responses to high-concentration sucrose taste. No such associations were observed with MID despite robust activation in those regions. Insula and supplementary motor area responses to intense sensations relate to a known risk factor for AUD in a way that is not apparent with a secondary (monetary) reward.

Brain response in heavy drinkers during cross-commodity alcohol and money discounting with potentially real rewards: A preliminary study.

Background: Alcohol use disorder (AUD) is associated with exaggerated preference for immediate rewards, a candidate endophenotype for use disorders. Addiction symptomology is often well-described by the preference for immediate intoxication over other delayed prosocial rewards. We measured brain activation in AUD-implicated regions during a cross-commodity delay discounting (CCD) task with choices for immediate alcohol and delayed money. Methods: Heavy drinkers (n=24) experienced a brief intravenous alcohol infusion prime, regained sobriety, then chose between 'One Shot' and delayed money in an adjusting delay CCD task (sober and intoxicated); also during fMRI (sober). Participants also performed a behavioral sensation seeking task and completed self-report inventories of other risk factors. We assessed brain activation to choices representing immediate intoxication versus delayed money rewards in a priori regions of interest defined within the framework of Addictions NeuroImaging Assessment. Results: Activation to CCD choice versus control trials activated paralimbic and ventral frontal cortical regions, including orbital and medial prefrontal cortex, posterior cingulate/retrosplenial cortex, angular and superior frontal gyri. We detected no differences between immediate or delayed choices. Left medial orbitofrontal cortex activation correlated with alcohol-induced wanting for alcohol; females showed greater activation than males. Behavioral sensation seeking correlated with right nucleus accumbens task engagement. Conclusions: Alcohol decision-making elicited activation in regions governing reward, introspection, and executive decision-making in heavy drinkers, demonstrating the utility of laboratory tasks designed to better model real-world choice. Our findings suggest that the brain processes subserving immediate and delayed choices are mostly overlapping, even with varied commodities.

Tangent functional connectomes uncover more unique phenotypic traits.

Functional connectomes (FCs) containing pairwise estimations of functional couplings between pairs of brain regions are commonly represented by correlation matrices. As symmetric positive definite matrices, FCs can be transformed via tangent space projections, resulting into tangent-FCs. Tangent-FCs have led to more accurate models predicting brain conditions or aging. Motivated by the fact that tangent-FCs seem to be better biomarkers than FCs, we hypothesized that tangent-FCs have also a higher fingerprint. We explored the effects of six factors: fMRI condition, scan length, parcellation granularity, reference matrix, main-diagonal regularization, and distance metric. Our results showed that identification rates are systematically higher when using tangent-FCs across the "fingerprint gradient" (here including test-retest, monozygotic and dizygotic twins). Highest identification rates were achieved when minimally (0.01) regularizing FCs while performing tangent space projection using Riemann reference matrix and using correlation distance to compare the resulting tangent-FCs. Such configuration was validated in a second dataset (resting-state).

Amyloid and tau pathology are associated with cerebral blood flow in a mixed sample of nondemented older adults with and without vascular risk factors for Alzheimer's disease.

Identification of biomarkers for the early stages of Alzheimer's disease (AD) is an imperative step in developing effective treatments. Cerebral blood flow (CBF) is a potential early biomarker for AD; generally, older adults with AD have decreased CBF compared to normally aging peers. CBF deviates as the disease process and symptoms progress. However, further characterization of the relationships between CBF and AD risk factors and pathologies is still needed. We assessed the relationships between CBF quantified by arterial spin-labeled magnetic resonance imaging, hypertension, APOEε4, and tau and amyloid positron emission tomography in 77 older adults: cognitively normal, subjective cognitive decline, and mild cognitive impairment. Tau and amyloid aggregation were related to altered CBF, and some of these relationships were dependent on hypertension or APOEε4 status. Our findings suggest a complex relationship between risk factors, AD pathologies, and CBF that warrants future studies of CBF as a potential early biomarker for AD.

Effects of acute alcohol exposure and chronic alcohol use on neurite orientation dispersion and density imaging (NODDI) parameters.

RATIONALE: Little is known about how acute and chronic alcohol exposure may alter the in vivo membrane properties of neurons. OBJECTIVES: We employed neurite orientation dispersion and density imaging (NODDI) to examine acute and chronic effects of alcohol exposure on neurite density. METHODS: Twenty-one healthy social drinkers (CON) and thirteen nontreatment-seeking individuals with alcohol use disorder (AUD) underwent a baseline multi-shell diffusion magnetic resonance imaging (dMRI) scan. A subset (10 CON, 5 AUD) received dMRI during intravenous infusions of saline and alcohol during dMRI. NODDI parametric images included orientation dispersion (OD), isotropic volume fraction (ISOVF), and corrected intracellular volume fraction (cICVF). Diffusion tensor imaging metrics of fractional anisotropy and mean, axial, and radial diffusivity (FA, MD, AD, RD) were also computed. Average parameter values were extracted from white matter (WM) tracts defined by the Johns Hopkins University atlas. RESULTS: There were group differences in FA, RD, MD, OD, and cICVF, primarily in the corpus callosum. Both saline and alcohol had effects on AD and cICVF in WM tracts proximal to the striatum, cingulate, and thalamus. This is the first work to indicate that acute fluid infusions may alter WM properties, which are conventionally believed to be insensitive to acute pharmacological challenges. It also suggests that the NODDI approach may be sensitive to transient changes in WM. The next steps should include determining if the effect on neurite density differs with solute or osmolality, or both, and translational studies to assess how alcohol and osmolality affect the efficiency of neurotransmission.

Assessing pulsatile waveforms of paravascular cerebrospinal fluid dynamics within the glymphatic pathways using dynamic diffusion-weighted imaging (dDWI)

Cerebrospinal fluid (CSF) in the paravascular spaces of the surface arteries (sPVS) is a vital pathway in brain waste clearance. Arterial pulsations may be the driving force of the paravascular flow, but its pulsatile pattern remains poorly characterized, and no clinically practical method for measuring its dynamics in the human brain is available. In this work, we introduce an imaging and quantification framework for in-vivo non-invasive assessment of pulsatile fluid dynamics in the sPVS. It used dynamic Diffusion-Weighted Imaging (dDWI) at a lower b-values of 150s/mm2 and retrospective gating to detect the slow flow of CSF while suppressing the fast flow of adjacent arterial blood. The waveform of CSF flow over a cardiac cycle was revealed by synchronizing the measurements with the heartbeat. A data-driven approach was developed to identify sPVS and allow automatic quantification of the whole-brain fluid waveforms. We applied dDWI to twenty-five participants aged 18-82 y/o. Results demonstrated that the fluid waveforms across the brain showed an explicit cardiac-cycle dependency, in good agreement with the vascular pumping hypothesis. Furthermore, the shape of the CSF waveforms closely resembled the pressure waveforms of the artery wall, suggesting that CSF dynamics is tightly related to artery wall mechanics. Finally, the CSF waveforms in aging participants revealed a strong age effect, with a significantly wider systolic peak observed in the older relative to younger participants. The peak widening may be associated with compromised vascular compliance and vessel wall stiffening in the older brain. Overall, the results demonstrate the feasibility, reproducibility, and sensitivity of dDWI for detecting sPVS fluid dynamics of the human brain. Our preliminary data suggest age-related alterations of the paravascular pumping. With an acquisition time of under six minutes, dDWI can be readily applied to study fluid dynamics in normal physiological conditions and cerebrovascular/neurodegenerative diseases.

Delay discounting and alcohol consumption correlate with dorsal anterior insula activation during choice in nontreatment-seeking heavy drinkers.

BACKGROUND: The anterior insular cortex (AIC), a prominent salience network node, integrates interoceptive information and emotional states into decision making. While AIC activation during delay discounting (DD) in alcohol use disorder (AUD) has been previously reported, the associations between AIC activation, impulsive choice, alcohol consumption, and connectivity remain unknown. We therefore tested AIC brain responses during DD in heavy drinkers and their association with DD performance, alcohol drinking, and task-based connectivity. METHODS: Twenty-nine heavy drinkers (12 females; mean (SD) age=31.5 ± 6.1 years; mean (SD)=40.8 ± 23.4 drinks/week) completed a DD task during functional MRI. Regions activated during DD decision making were tested for correlation with DD behavior and alcohol drinking. Psychophysiological interaction (PPI) models assessed the task-dependent functional connectivity (FC) of activation during choice. RESULTS: Delay discounting choice activated bilateral anterior insular cortex, anterior cingulate cortex, and left precentral gyrus. Right dorsal (d) AIC activation during choice negatively correlated withdiscounting of delayed rewards and alcohol consumption. PPI analysis revealed FC of the right dAIC to both the anterior and posterior cingulate cortices-key nodes in the midline default mode network. CONCLUSIONS: Greater dAIC involvement in intertemporal choice may confer more adaptive behavior (lower impulsivity and alcohol consumption). Moreover, salience network processes governing discounting may require midline default mode (precuneus/posterior cingulate cortex) recruitment. These findings supporta key adaptive role for right dAIC in decision making involving future rewards and risky drinking.

Altered corollary discharge in the auditory cortex could reflect louder inner voice experience in patients with verbal hallucinations, a pilot fMRI study.

INTRODUCTION: Wide range of evidence associates auditory verbal hallucinations (AVH) with frontotemporal corollary discharge deficit. AVH likely reflect altered experiences of the inner voice and are phenomenologically diverse. The aspects of hallucinations (and related inner voice experiences) that could be explained by this deficit remain unclear. To address this important subject, we examined the temporal cortex activity during two tasks with and without corollary discharge. METHODS: We carried out an event-related BOLD fMRI study to examine temporal cortex activity in seven patients and eight healthy controls during two tasks with and without corollary discharge: reading aloud and hearing, respectively. Data were denoised by removing independent components related to head movement and subsequently processed using finite impulse response basis function to address hemodynamic response variations. To mitigate the small sample size, final analyses were carried out using permutation-based analysis of variance. RESULTS: There was a significant group interaction in the Read relative to Hear condition during the early post-stimulus stage in the left Heschl's Gyrus (p < 0.01, corrected for multiple comparisons, at peak voxel [-72,53,41]). This effect was driven by a higher activity in the Read relative to the Hear condition in the same area in the patients (p < 0.02, corrected). CONCLUSIONS: Our results are consistent with prior literature indicating abnormal frontotemporal disconnection in participants with hallucinations. The functional repercussions of this deficit were limited to the primary auditory cortex in early post-stimulus stage, which suggests louder experience of the inner voice in patients and could account for the loudness of their hallucinations.

Cerebral Blood Flow in the Salience Network of Individuals with Alcohol Use Disorder.

AIMS: Magnetic resonance imaging (MRI) studies have identified structural and functional differences in salience network nodes of individuals with alcohol use disorders (AUDs) after chronic exposure to alcohol. However, no studies have investigated cerebral blood flow (CBF) in nontreatment-seeking (NTS) individuals with AUD. METHODS: In this work, we sought to quantify putative CBF deficits in NTS individuals relative to social drinking (SD) controls and determine if CBF in the salience network is associated with AUD severity. Fifteen NTS (36.5 ± 11.2 years old, 30.0 ± 22.7 drinks/week) and 22 SD (35.6 ± 11.9 years old, 9.1 ± 5.7 drinks/week) underwent pseudocontinuous arterial spin labeling MRI. RESULTS: Compared with social drinkers, NTS individuals had significantly lower CBF in the right and left dorsal anterior insula, and the left ventral anterior and posterior insula. The Alcohol Use Disorder Identification Test (AUDIT) score showed a significant negative relationship with CBF in the bilateral caudal anterior cingulate cortex. In addition, a significant negative correlation was present between number of standard drinks consumed per week and the left frontal opercular CBF. CONCLUSION: These results provide evidence that insular CBF is negatively associated with heavy drinking, and that severity of alcohol use is related to CBF deficits in key nodes of the salience network. Longitudinal data are needed to understand if disruptions of CBF in the insula and the salience network are a predisposition for or a consequence of chronic AUD.

A morphospace of functional configuration to assess configural breadth based on brain functional networks.

The quantification of human brain functional (re)configurations across varying cognitive demands remains an unresolved topic. We propose that such functional configurations may be categorized into three different types: (a) network configural breadth, (b) task-to task transitional reconfiguration, and (c) within-task reconfiguration. Such functional reconfigurations are rather subtle at the whole-brain level. Hence, we propose a mesoscopic framework focused on functional networks (FNs) or communities to quantify functional (re)configurations. To do so, we introduce a 2D network morphospace that relies on two novel mesoscopic metrics, trapping efficiency (TE) and exit entropy (EE), which capture topology and integration of information within and between a reference set of FNs. We use this framework to quantify the network configural breadth across different tasks. We show that the metrics defining this morphospace can differentiate FNs, cognitive tasks, and subjects. We also show that network configural breadth significantly predicts behavioral measures, such as episodic memory, verbal episodic memory, fluid intelligence, and general intelligence. In essence, we put forth a framework to explore the cognitive space in a comprehensive manner, for each individual separately, and at different levels of granularity. This tool that can also quantify the FN reconfigurations that result from the brain switching between mental states.

Brain responses during delay discounting in youth at high-risk for substance use disorders.

Offspring of parents with substance use disorders (SUD) discount future rewards at a steeper rate on the monetary delay discounting task (DD) than typically developing youth. However, brain activation during DD has yet to be studied in drug naïve youth with a family history (FH) of SUD. Here, we investigate brain activation differences in high-risk youth during DD. We recruited substance naïve youth, aged 11-12, into three groups to compare brain activation during DD: (1) High-risk youth (n = 35) with a FH of SUD and externalizing psychiatric disorders, (2) psychiatric controls (n = 25) who had no FH of SUD, but with equivalent externalizing psychiatric disorders as high-risk youth, and (3) a healthy control group (n = 24) with no FH of SUD and minimal psychopathology. A whole-brain voxel wise analysis of the [Delay > Baseline], [Immediate > Baseline], and [Control > Baseline] contrasts identified functional regions of interest, from which extracted parameter estimates were tested for significant group differences. Relative to control youth, high-risk youth showed stronger activation in the left posterior insula and thalamus when making delayed choices, and stronger activation of the parahippocampal gyrus when making both delayed and control choices (ps < 0.05). Activation in the left posterior insula negatively correlated with both subscales of the Emotion Regulation Checklist, and positively correlated with the Stroop interference effect (ps < 0.05). Our findings suggest possible heritable SUD risk neural markers that distinguish drug naïve high-risk youth from psychiatric and healthy controls.

Anterior cingulate cortex metabolites and white matter microstructure: a multimodal study of emergent alcohol use disorder.

Multimodal imaging is increasingly used to address neuropathology associated with alcohol use disorder (AUD). Few studies have investigated relationships between metabolite concentrations and white matter (WM) integrity; currently, there are no such data in AUD. In this preliminary study, we used complementary neuroimaging techniques, magnetic resonance spectroscopy (MRS), and diffusion weighted imaging (DWI), to study AUD neurophysiology. We tested for relationships between metabolites in the dorsal anterior cingulate cortex (dACC) and adjacent WM microstructure in young adult AUD and control (CON) subjects. Sixteen AUD and fourteen CON underwent whole-brain DWI and MRS of the dACC. Outcomes were dACC metabolites, and diffusion tensor metrics of dACC-adjacent WM. Multiple linear regression terms included WM region, group, and region × group for prediction of dACC metabolites. dACC myo-inositol was positively correlated with axial diffusivity in the left anterior corona radiata (p < 0.0001) in CON but not AUD (group effect: p < 0.001; region × group: p < 0.001; Bonferroni-corrected). In the bilateral anterior corona radiata and right genu of the corpus callosum, glutamate was negatively related to mean diffusivity in AUD, but not CON subjects (all model terms: p < 0.05, uncorrected). In AUD subjects, dACC glutamate was negatively correlated with AUD symptom severity. This is likely the first integrative study of cortical metabolites and WM integrity in young individuals with AUD. Differential relationships between dACC metabolites and adjacent WM tract integrity in AUD could represent early consequences of hazardous drinking, and/or novel biomarkers of early-stage AUD. Additional studies are required to replicate these findings, and to determine the behavioral relevance of these results.

Neural correlates of inhibitory control are associated with stimulant-like effects of alcohol.

Poor inhibitory control and heightened feelings of stimulation after alcohol are two well-established risk factors for alcohol use disorder (AUD). Although these risk factors have traditionally been viewed as orthogonal, recent evidence suggests that the two are related and may share common neurobiological mechanisms. Here we examined the degree to which neural activity during inhibition was associated with subjective reports of stimulation following alcohol. To assess neural changes during inhibition, moderate alcohol drinkers performed a stop signal task during fMRI without drug. To assess subjective responses to alcohol they ingested alcohol (0.8 g/kg) or placebo beverages under double-blind conditions and provided subjective reports of stimulation and sedation. Feelings of stimulation following alcohol were inversely associated with activity in the supplementary motor area, insula, and middle frontal gyrus during inhibition (successful stop trials compared to go trials). Feelings of sedation did not correlate with brain activation. These results extend previous findings suggesting that poor inhibitory control is associated with more positive subjective responses to alcohol. These interrelated risk factors may contribute to susceptibility to future excessive alcohol use, and ultimately lead to neurobiological targets to prevent or treat AUD.

Optimizing differential identifiability improves connectome predictive modeling of cognitive deficits from functional connectivity in Alzheimer's disease.

Functional connectivity, as estimated using resting state functional MRI, has shown potential in bridging the gap between pathophysiology and cognition. However, clinical use of functional connectivity biomarkers is impeded by unreliable estimates of individual functional connectomes and lack of generalizability of models predicting cognitive outcomes from connectivity. To address these issues, we combine the frameworks of connectome predictive modeling and differential identifiability. Using the combined framework, we show that enhancing the individual fingerprint of resting state functional connectomes leads to robust identification of functional networks associated to cognitive outcomes and also improves prediction of cognitive outcomes from functional connectomes. Using a comprehensive spectrum of cognitive outcomes associated to Alzheimer's disease (AD), we identify and characterize functional networks associated to specific cognitive deficits exhibited in AD. This combined framework is an important step in making individual level predictions of cognition from resting state functional connectomes and in understanding the relationship between cognition and connectivity.

Keeping the inner voice inside the head, a pilot fMRI study.

INTRODUCTION: The inner voice is experienced during thinking in words (inner speech) and silent reading and evokes brain activity that is highly similar to that associated with external voices. Yet while the inner voice is experienced in internal space (inside the head), external voices (one's own and those of others) are experienced in external space. In this paper, we investigate the neural basis of this differential spatial localization. METHODS: We used fMRI to examine the difference in brain activity between reading silently and reading aloud. As the task involved reading aloud, data were first denoised by removing independent components related to head movement. They were subsequently processed using finite impulse response basis function to address the variations of the hemodynamic response. Final analyses were carried out using permutation-based statistics, which is appropriate for small samples. These analyses produce spatiotemporal maps of brain activity. RESULTS: Reading silently relative to reading aloud was associated with activity of the "where" auditory pathway (Inferior parietal lobule and middle temporal gyrus), and delayed activity of the primary auditory cortex. CONCLUSIONS: These pilot data suggest that internal space localization of the inner voice depends on the same neural resources as that for external space localization of external voices-the "where" auditory pathway. We discuss the implications of these findings on the possible mechanisms of abnormal experiences of the inner voice as is the case in verbal hallucinations.

Connectivity-informed adaptive regularization for generalized outcomes.

One of the challenging problems in neuroimaging is the principled incorporation of information from different imaging modalities. Data from each modality are frequently analyzed separately using, for instance, dimensionality reduction techniques, which result in a loss of mutual information. We propose a novel regularization method, generalized ridgified Partially Empirical Eigenvectors for Regression (griPEER), to estimate associations between the brain structure features and a scalar outcome within the generalized linear regression framework. griPEER improves the regression coefficient estimation by providing a principled approach to use external information from the structural brain connectivity. Specifically, we incorporate a penalty term, derived from the structural connectivity Laplacian matrix, in the penalized generalized linear regression. In this work, we address both theoretical and computational issues and demonstrate the robustness of our method despite incomplete information about the structural brain connectivity. In addition, we also provide a significance testing procedure for performing inference on the estimated coefficients. Finally, griPEER is evaluated both in extensive simulation studies and using clinical data to classify HIV+ and HIV- individuals.

L'un des défis en imagerie cérébrale consiste à établir les principes pour incorporer de l'information provenant de différentes modalités d'imagerie. Les données de chaque modalité sont fréquemment analysées séparément, exploitant par exemple des techniques de réduction de la dimension, ce qui conduit à une perte d'information mutuelle. Les auteurs proposent une nouvelle méthode de régularisation, griPEER (ou par vecteurs propres ridgifiés partiellement empiriques généralisés pour la régression) afin d'estimer l'association entre des caratéristiques de structures du cerveau et une variable réponse scalaire dans le cadre d'une régression linéaire généralisée. Les griPEER améliorent l'estimation des coefficients de régression en établissant les principes d'une approche permettant d'utiliser des informations externes de connectivité des structures du cerveau. À cet effet, les auteurs ajoutent au modèle de régression pénalisée généralisé un terme de pénalité dérivé de la matrice laplacienne de connectivité structurelle. Les auteurs résolvent des problèmes théoriques et calculatoires, puis démontrent la robustesse de leur méthode lorsque l'information à propos de la connectivité du cerveau est incomplète. De plus, ils présentent une procédure de test d'hypothèse permettant de l'inférence au sujet des paramètres estimés. Finalement, les auteurs évaluent les griPEER dans de vastes études de simulation et en utilisant des données cliniques afin de classifier les individus en VIH+ et VIH−.

The disengaging brain: Dynamic transitions from cognitive engagement and alcoholism risk.

Human functional brain connectivity is usually measured either at "rest" or during cognitive tasks, ignoring life's moments of mental transition. We propose a different approach to understanding brain network transitions. We applied a novel independent component analysis of functional connectivity during motor inhibition (stop signal task) and during the continuous transition to an immediately ensuing rest. A functional network reconfiguration process emerged that: (i) was most prominent in those without familial alcoholism risk, (ii) encompassed brain areas engaged by the task, yet (iii) appeared only transiently after task cessation. The pattern was not present in a pre-task rest scan or in the remaining minutes of post-task rest. Finally, this transient network reconfiguration related to a key behavioral trait of addiction risk: reward delay discounting. These novel findings illustrate how dynamic brain functional reconfiguration during normally unstudied periods of cognitive transition might reflect addiction vulnerability, and potentially other forms of brain dysfunction.