Brain aerobic glycolysis and resilience in Alzheimer disease.

The distribution of brain aerobic glycolysis (AG) in normal young adults correlates spatially with amyloid-beta (Aß) deposition in individuals with symptomatic and preclinical Alzheimer disease (AD). Brain AG decreases with age, but the functional significance of this decrease with regard to the development of AD symptomatology is poorly understood. Using PET measurements of regional blood flow, oxygen consumption, and glucose utilization-from which we derive AG-we find that cognitive impairment is strongly associated with loss of the typical youthful pattern of AG. In contrast, amyloid positivity without cognitive impairment was associated with preservation of youthful brain AG, which was even higher than that seen in cognitively unimpaired, amyloid negative adults. Similar findings were not seen for blood flow nor oxygen consumption. Finally, in cognitively unimpaired adults, white matter hyperintensity burden was found to be specifically associated with decreased youthful brain AG. Our results suggest that AG may have a role in the resilience and/or response to early stages of amyloid pathology and that age-related white matter disease may impair this process.

Inferring the dynamical effects of stroke lesions through whole-brain modeling.

Understanding the effect of focal lesions (stroke) on brain structure-function traditionally relies on behavioral analyses and correlation with neuroimaging data. Here we use structural disconnection maps from individual lesions to derive a causal mechanistic generative whole-brain model able to explain both functional connectivity alterations and behavioral deficits induced by stroke. As compared to other models that use only the local lesion information, the similarity to the empirical fMRI connectivity increases when the widespread structural disconnection information is considered. The presented model classifies behavioral impairment severity with higher accuracy than other types of information (e.g.: functional connectivity). We assessed topological measures that characterize the functional effects of damage. With the obtained results, we were able to understand how network dynamics change emerge, in a nontrivial way, after a stroke injury of the underlying complex brain system. This type of modeling, including structural disconnection information, helps to deepen our understanding of the underlying mechanisms of stroke lesions.

Spontaneous activity patterns in human motor cortex replay evoked activity patterns for hand movements.

Spontaneous brain activity, measured with resting state fMRI (R-fMRI), is correlated among regions that are co-activated by behavioral tasks. It is unclear, however, whether spatial patterns of spontaneous activity within a cortical region correspond to spatial patterns of activity evoked by specific stimuli, actions, or mental states. The current study investigated the hypothesis that spontaneous activity in motor cortex represents motor patterns commonly occurring in daily life. To test this hypothesis 15 healthy participants were scanned while performing four different hand movements. Three movements (Grip, Extend, Pinch) were ecological involving grip and grasp hand movements; one control movement involving the rotation of the wrist was not ecological and infrequent (Shake). They were also scanned at rest before and after the execution of the motor tasks (resting-state scans). Using the task data, we identified movement-specific patterns in the primary motor cortex. These task-defined patterns were compared to resting-state patterns in the same motor region. We also performed a control analysis within the primary visual cortex. We found that spontaneous activity patterns in the primary motor cortex were more like task patterns for ecological than control movements. In contrast, there was no difference between ecological and control hand movements in the primary visual area. These findings provide evidence that spontaneous activity in human motor cortex forms fine-scale, patterned representations associated with behaviors that frequently occur in daily life.

Subcortical-cortical dynamical states of the human brain and their breakdown in stroke.

The mechanisms controlling dynamical patterns in spontaneous brain activity are poorly understood. Here, we provide evidence that cortical dynamics in the ultra-slow frequency range (<0.01-0.1 Hz) requires intact cortical-subcortical communication. Using functional magnetic resonance imaging (fMRI) at rest, we identify Dynamic Functional States (DFSs), transient but recurrent clusters of cortical and subcortical regions synchronizing at ultra-slow frequencies. We observe that shifts in cortical clusters are temporally coincident with shifts in subcortical clusters, with cortical regions flexibly synchronizing with either limbic regions (hippocampus/amygdala), or subcortical nuclei (thalamus/basal ganglia). Focal lesions induced by stroke, especially those damaging white matter connections between basal ganglia/thalamus and cortex, provoke anomalies in the fraction times, dwell times, and transitions between DFSs, causing a bias toward abnormal network integration. Dynamical anomalies observed 2 weeks after stroke recover in time and contribute to explaining neurological impairment and long-term outcome.

Lesion Quantification Toolkit: A MATLAB software tool for estimating grey matter damage and white matter disconnections in patients with focal brain lesions.

Lesion studies are an important tool for cognitive neuroscientists and neurologists. However, while brain lesion studies have traditionally aimed to localize neurological symptoms to specific anatomical loci, a growing body of evidence indicates that neurological diseases such as stroke are best conceptualized as brain network disorders. While researchers in the fields of neuroscience and neurology are therefore increasingly interested in quantifying the effects of focal brain lesions on the white matter connections that form the brain's structural connectome, few dedicated tools exist to facilitate this endeavor. Here, we present the Lesion Quantification Toolkit, a publicly available MATLAB software package for quantifying the structural impacts of focal brain lesions. The Lesion Quantification Toolkit uses atlas-based approaches to estimate parcel-level grey matter lesion loads and multiple measures of white matter disconnection severity that include tract-level disconnection measures, voxel-wise disconnection maps, and parcel-wise disconnection matrices. The toolkit also estimates lesion-induced increases in the lengths of the shortest structural paths between parcel pairs, which provide information about changes in higher-order structural network topology. We describe in detail each of the different measures produced by the toolkit, discuss their applications and considerations relevant to their use, and perform example analyses using real behavioral data collected from sub-acute stroke patients. We show that analyses performed using the different measures produced by the toolkit produce results that are highly consistent with results that have been reported in the prior literature, and we demonstrate the consistency of results obtained from analyses conducted using the different disconnection measures produced by the toolkit. We anticipate that the Lesion Quantification Toolkit will empower researchers to address research questions that would be difficult or impossible to address using traditional lesion analyses alone, and ultimately, lead to advances in our understanding of how white matter disconnections contribute to the cognitive, behavioral, and physiological consequences of focal brain lesions.

Spontaneously emerging patterns in human visual cortex and their functional connectivity are linked to the patterns evoked by visual stimuli.

The function of spontaneous brain activity is an important issue in neuroscience. Here we test the hypothesis that patterns of spontaneous activity code representational patterns evoked by stimuli. We compared in human visual cortex multivertex patterns of spontaneous activity to patterns evoked by ecological visual stimuli (faces, bodies, scenes) and low-level visual features (e.g., phase-scrambled faces). Specifically, we identified regions that preferred particular stimulus categories during localizer scans (e.g., extrastriate body area for bodies), measured multivertex patterns for each category during event-related task scans, and then correlated over vertices these stimulus-evoked patterns to the pattern measured on each frame of resting-state scans. The mean correlation coefficient was essentially zero for all regions/stimulus categories, indicating that resting multivertex patterns were not biased toward particular stimulus-evoked patterns. However, the spread of correlation coefficients between stimulus-evoked and resting patterns, positive and negative, was significantly greater for the preferred stimulus category of an ROI. The relationship between spontaneous and stimulus-evoked multivertex patterns also governed the temporal correlation or functional connectivity of patterns of spontaneous activity between individual regions (pattern-based functional connectivity). Resting multivertex patterns related to an object category fluctuated preferentially between ROIs preferring the same category, and fluctuations of the pattern for a category (e.g., body) within its preferred ROIs were largely uncorrelated with fluctuations of the pattern for a disparate category (e.g., scene) within its preferred ROIs. These results support the proposal that spontaneous multivertex activity patterns are linked to stimulus-evoked patterns, consistent with a representational function for spontaneous activity.NEW & NOTEWORTHY Spontaneous brain activity was once thought to reflect only noise, but evidence of strong spatiotemporal regularities has motivated a search for functional explanations. Here we show that the spatial pattern of spontaneous activity in human high-level and early visual cortex is related to the spatial patterns evoked by stimuli. Moreover, these patterns partly govern spontaneous spatiotemporal interactions between regions, so-called functional connectivity. These results support the hypothesis that spontaneous activity serves a representational function.

Damage to the shortest structural paths between brain regions is associated with disruptions of resting-state functional connectivity after stroke.

Focal brain lesions disrupt resting-state functional connectivity, but the underlying structural mechanisms are unclear. Here, we examined the direct and indirect effects of structural disconnections on resting-state functional connectivity in a large sample of sub-acute stroke patients with heterogeneous brain lesions. We estimated the impact of each patient's lesion on the structural connectome by embedding the lesion in a diffusion MRI streamline tractography atlas constructed using data from healthy individuals. We defined direct disconnections as the loss of direct structural connections between two regions, and indirect disconnections as increases in the shortest structural path length between two regions that lack direct structural connections. We then tested the hypothesis that functional connectivity disruptions would be more severe for disconnected regions than for regions with spared connections. On average, nearly 20% of all region pairs were estimated to be either directly or indirectly disconnected by the lesions in our sample, and extensive disconnections were associated primarily with damage to deep white matter locations. Importantly, both directly and indirectly disconnected region pairs showed more severe functional connectivity disruptions than region pairs with spared direct and indirect connections, respectively, although functional connectivity disruptions tended to be most severe between region pairs that sustained direct structural disconnections. Together, these results emphasize the widespread impacts of focal brain lesions on the structural connectome and show that these impacts are reflected by disruptions of the functional connectome. Further, they indicate that in addition to direct structural disconnections, lesion-induced increases in the structural shortest path lengths between indirectly structurally connected region pairs provide information about the remote functional disruptions caused by focal brain lesions.

Structural Disconnections Explain Brain Network Dysfunction after Stroke.

Stroke causes focal brain lesions that disrupt functional connectivity (FC), a measure of activity synchronization, throughout distributed brain networks. It is often assumed that FC disruptions reflect damage to specific cortical regions. However, an alternative explanation is that they reflect the structural disconnection (SDC) of white matter pathways. Here, we compare these explanations using data from 114 stroke patients. Across multiple analyses, we find that SDC measures outperform focal damage measures, including damage to putative critical cortical regions, for explaining FC disruptions associated with stroke. We also identify a core mode of structure-function covariation that links the severity of interhemispheric SDCs to widespread FC disruptions across patients and that correlates with deficits in multiple behavioral domains. We conclude that a lesion's impact on the structural connectome is what determines its impact on FC and that interhemispheric SDCs may play a particularly important role in mediating FC disruptions after stroke.

Brain networks' functional connectivity separates aphasic deficits in stroke.

OBJECTIVE: To investigate whether different language deficits are distinguished by the relative strengths of their association with the functional connectivity (FC) at rest of the language network (LN) and cingulo-opercular network (CON) after aphasic stroke. METHODS: In a group of patients with acute stroke and left-hemisphere damage, we identified 3 distinct, yet correlated, clusters of deficits including comprehension/lexical semantic, grapheme-phoneme knowledge, and verbal executive functions. We computed partial correlations in which the contributions of a behavioral cluster and network FC of no interest were statistically regressed out. RESULTS: We observed a double dissociation such that impairment of grapheme-phoneme knowledge was more associated with lower FC of the LN within the left hemisphere than lower FC of the CON, whereas verbal executive deficits were more related to lower FC of the CON than the LN in the left hemisphere. Furthermore, the specific association between language deficits and FC was independent of the amount of structural damage to the LN and CON. CONCLUSION: These findings indicate that after a left-hemisphere lesion, the type of language impairment is related to the abnormal pattern of correlated activity in different networks. Accordingly, they extend the concept of a neuropsychological double dissociation from structural damage to functional network abnormalities. Finally, current results strongly argue in favor of the behavioral specificity of intrinsic brain activity after focal structural damage.

Stronger prediction of motor recovery and outcome post-stroke by cortico-spinal tract integrity than functional connectivity.

OBJECTIVES: To examine longitudinal changes in structural and functional connectivity post-stroke in patients with motor impairment, and define their importance for recovery and outcome at 12 months. METHODS: First-time stroke patients (N = 31) were studied at 1-2 weeks, 3 months, and 12 months post-injury with a validated motor battery and resting-state fMRI to measure inter-hemispheric functional connectivity (FC). Fractional anisotropy (FA) of the cortico-spinal tract (CST) was derived from diffusion tensor imaging as a measure of white matter organization. ANOVAs were used to test for changes in FC, FA, and motor performance scores over time, and regression analysis related motor outcome to clinical and neuroimaging variables. RESULTS: FA of the ipsilesional CST improved significantly from 3 to 12 months and was strongly correlated with motor performance. FA improved even in the absence of direct damage to the CST. Inter-hemispheric FC also improved over time, but did not correlate with motor performance at 12 months. Clinical variables (early motor score, education level, and age) predicted 80.4% of the variation of motor outcome, and FA increased the predictability to 84.6%. FC did not contribute to the prediction of motor outcome. CONCLUSIONS: Stroke causes changes to the CST microstructure that can account for behavioral variability even in the absence of demonstrable lesion. Ipsilesional CST undergoes remodeling post-stroke, even past the three-month window when most of the motor recovery happens. FA of the CST, but not inter-hemispheric FC, can improve to the prediction of motor outcome based on early motor scores.

Distinct phase-amplitude couplings distinguish cognitive processes in human attention.

Spatial attention is the cognitive function that coordinates the selection of visual stimuli with appropriate behavioral responses. Recent studies have reported that phase-amplitude coupling (PAC) of low and high frequencies covaries with spatial attention, but differ on the direction of covariation and the frequency ranges involved. We hypothesized that distinct phase-amplitude frequency pairs have differentiable contributions during tasks that manipulate spatial attention. We investigated this hypothesis with electrocorticography (ECoG) recordings from participants who engaged in a cued spatial attention task. To understand the contribution of PAC to spatial attention we classified cortical sites by their relationship to spatial variables or behavioral performance. Local neural activity in spatial sites was sensitive to spatial variables in the task, while local neural activity in behavioral sites correlated with reaction time. We found two PAC frequency clusters that covaried with different aspects of the task. During a period of cued attention, delta-phase/high-gamma (DH) PAC was sensitive to cue direction in spatial sites. In contrast, theta-alpha-phase/beta-low-gamma-amplitude (TABL) PAC robustly correlated with future reaction times in behavioral sites. Finally, we investigated the origins of TABL PAC and found it corresponded to behaviorally relevant, sharp waveforms, which were also coupled to a low frequency rhythm. We conclude that TABL and DH PAC correspond to distinct mechanisms during spatial attention tasks and that sharp waveforms are elements of a coupled dynamical process.

Differential white matter involvement associated with distinct visuospatial deficits after right hemisphere stroke.

Visuospatial attention depends on the integration of multiple processes, and people with right hemisphere lesions after a stroke may exhibit severe or no visuospatial deficits. The anatomy of core components of visuospatial attention is an area of intense interest. Here we examine the relationship between the disruption of core components of attention and lesion distribution in a heterogeneous group (N = 70) of patients with right hemisphere strokes regardless of the presence of clinical neglect. Deficits of lateralized spatial orienting, measured as the difference in reaction times for responding to visual targets in the contralesional or ipsilesional visual field, and deficits in re-orienting attention, as measured by the difference in reaction times for invalidly versus validly cued targets, were measured using a computerized spatial orienting task. Both measures were related through logistic regression and a novel ridge regression method to anatomical damage measured with magnetic resonance imaging. While many regions were common to both deficit maps, a deficit in lateralized spatial orienting was more associated with lesions in the white matter underlying the posterior parietal cortex, and middle and inferior frontal gyri. A deficit in re-orienting of attention toward unattended locations was associated with lesions in the white matter of the posterior parietal cortex, insular cortex and less so with white matter involvement of the anterior frontal lobe. An hodological analysis also supports this partial dissociation between the white matter tracts that are damaged in lateralized spatial biases versus impaired re-orienting. Our results underscore that the integrity of fronto-parietal white matter tracts is crucial for visuospatial attention and that different attention components are mediated by partially distinct neuronal substrates.

Disruptions of network connectivity predict impairment in multiple behavioral domains after stroke.

Deficits following stroke are classically attributed to focal damage, but recent evidence suggests a key role of distributed brain network disruption. We measured resting functional connectivity (FC), lesion topography, and behavior in multiple domains (attention, visual memory, verbal memory, language, motor, and visual) in a cohort of 132 stroke patients, and used machine-learning models to predict neurological impairment in individual subjects. We found that visual memory and verbal memory were better predicted by FC, whereas visual and motor impairments were better predicted by lesion topography. Attention and language deficits were well predicted by both. Next, we identified a general pattern of physiological network dysfunction consisting of decrease of interhemispheric integration and intrahemispheric segregation, which strongly related to behavioral impairment in multiple domains. Network-specific patterns of dysfunction predicted specific behavioral deficits, and loss of interhemispheric communication across a set of regions was associated with impairment across multiple behavioral domains. These results link key organizational features of brain networks to brain-behavior relationships in stroke.

Early diffusion evidence of retrograde transsynaptic degeneration in the human visual system.

OBJECTIVE: We investigated whether diffusion tensor imaging (DTI) indices of white matter integrity would offer early markers of retrograde transsynaptic degeneration (RTD) in the visual system after stroke. METHODS: We performed a prospective longitudinal analysis of the sensitivity of DTI markers of optic tract health in 12 patients with postsynaptic visual pathway stroke, 12 stroke controls, and 28 healthy controls. We examined group differences in (1) optic tract fractional anisotropy (FA-asymmetry), (2) perimetric measures of visual impairment, and (3) the relationship between FA-asymmetry and perimetric assessment. RESULTS: FA-asymmetry was higher in patients with visual pathway lesions than in control groups. These differences were evident 3 months from the time of injury and did not change significantly at 12 months. Perimetric measures showed evidence of impairment in participants with visual pathway stroke but not in control groups. A significant association was observed between FA-asymmetry and perimetric measures at 3 months, which persisted at 12 months. CONCLUSIONS: DTI markers of RTD are apparent 3 months from the time of injury. This represents the earliest noninvasive evidence of RTD in any species. Furthermore, these measures associate with measures of visual impairment. DTI measures offer a reproducible, noninvasive, and sensitive method of investigating RTD and its role in visual impairment.

Normalization of network connectivity in hemispatial neglect recovery.

OBJECTIVE: We recently reported that spatial and nonspatial attention deficits in stroke patients with hemispatial neglect are correlated at 2 weeks postonset with widespread alterations of interhemispheric and intrahemispheric functional connectivity (FC) measured with resting-state functional magnetic resonance imaging across multiple brain networks. The mechanisms underlying neglect recovery are largely unknown. In this study, we test the hypothesis that recovery of hemispatial neglect correlates with a return of network connectivity toward a normal pattern, herein defined as "network normalization." METHODS: We measured attention deficits with a neuropsychological battery and FC in a large cohort of stroke patients at, on average, 2 weeks (n = 99), 3 months (n = 77), and 12 months (n = 64) postonset. The relationship between behavioral improvement and changes in FC was analyzed both in terms of a priori regions and networks known to be abnormal subacutely and in a data-driven manner. RESULTS: Attention deficit recovery was mostly complete by 3 months and was significantly correlated with a normalization of abnormal FC across many networks. Improvement of attention deficits, independent of initial severity, was correlated with improvements of previously depressed interhemispheric FC across attention, sensory, and motor networks, and a restoration of the normal anticorrelation between dorsal attention/motor regions and default-mode/frontoparietal regions, particularly in the damaged hemisphere. INTERPRETATION: These results demonstrate that abnormal network connectivity in hemispatial neglect is behaviorally relevant. A return toward normal network interactions, and presumably optimal information processing, is therefore a systems-level mechanism that is associated with improvements of attention over time after focal injury. Ann Neurol 2016;80:127-141.

Dissociated functional connectivity profiles for motor and attention deficits in acute right-hemisphere stroke.

Strokes often cause multiple behavioural deficits that are correlated at the population level. Here, we show that motor and attention deficits are selectively associated with abnormal patterns of resting state functional connectivity in the dorsal attention and motor networks. We measured attention and motor deficits in 44 right hemisphere-damaged patients with a first-time stroke at 1-2 weeks post-onset. The motor battery included tests that evaluated deficits in both upper and lower extremities. The attention battery assessed both spatial and non-spatial attention deficits. Summary measures for motor and attention deficits were identified through principal component analyses on the raw behavioural scores. Functional connectivity in structurally normal cortex was estimated based on the temporal correlation of blood oxygenation level-dependent signals measured at rest with functional magnetic resonance imaging. Any correlation between motor and attention deficits and between functional connectivity in the dorsal attention network and motor networks that might spuriously affect the relationship between each deficit and functional connectivity was statistically removed. We report a double dissociation between abnormal functional connectivity patterns and attention and motor deficits, respectively. Attention deficits were significantly more correlated with abnormal interhemispheric functional connectivity within the dorsal attention network than motor networks, while motor deficits were significantly more correlated with abnormal interhemispheric functional connectivity patterns within the motor networks than dorsal attention network. These findings indicate that functional connectivity patterns in structurally normal cortex following a stroke link abnormal physiology in brain networks to the corresponding behavioural deficits.

Abnormal White Matter Blood-Oxygen-Level-Dependent Signals in Chronic Mild Traumatic Brain Injury.

Concussion, or mild traumatic brain injury (mTBI), can cause persistent behavioral symptoms and cognitive impairment, but it is unclear if this condition is associated with detectable structural or functional brain changes. At two sites, chronic mTBI human subjects with persistent post-concussive symptoms (three months to five years after injury) and age- and education-matched healthy human control subjects underwent extensive neuropsychological and visual tracking eye movement tests. At one site, patients and controls also performed the visual tracking tasks while blood-oxygen-level-dependent (BOLD) signals were measured with functional magnetic resonance imaging. Although neither neuropsychological nor visual tracking measures distinguished patients from controls at the level of individual subjects, abnormal BOLD signals were reliably detected in patients. The most consistent changes were localized in white matter regions: anterior internal capsule and superior longitudinal fasciculus. In contrast, BOLD signals were normal in cortical regions, such as the frontal eye field and intraparietal sulcus, that mediate oculomotor and attention functions necessary for visual tracking. The abnormal BOLD signals accurately differentiated chronic mTBI patients from healthy controls at the single-subject level, although they did not correlate with symptoms or neuropsychological performance. We conclude that subjects with persistent post-concussive symptoms can be identified years after their TBI using fMRI and an eye movement task despite showing normal structural MRI and DTI.

Large-scale changes in network interactions as a physiological signature of spatial neglect.

The relationship between spontaneous brain activity and behaviour following focal injury is not well understood. Here, we report a large-scale study of resting state functional connectivity MRI and spatial neglect following stroke in a large (n=84) heterogeneous sample of first-ever stroke patients (within 1-2 weeks). Spatial neglect, which is typically more severe after right than left hemisphere injury, includes deficits of spatial attention and motor actions contralateral to the lesion, and low general attention due to impaired vigilance/arousal. Patients underwent structural and resting state functional MRI scans, and spatial neglect was measured using the Posner spatial cueing task, and Mesulam and Behavioural Inattention Test cancellation tests. A principal component analysis of the behavioural tests revealed a main factor accounting for 34% of variance that captured three correlated behavioural deficits: visual neglect of the contralesional visual field, visuomotor neglect of the contralesional field, and low overall performance. In an independent sample (21 healthy subjects), we defined 10 resting state networks consisting of 169 brain regions: visual-fovea and visual-periphery, sensory-motor, auditory, dorsal attention, ventral attention, language, fronto-parietal control, cingulo-opercular control, and default mode. We correlated the neglect factor score with the strength of resting state functional connectivity within and across the 10 resting state networks. All damaged brain voxels were removed from the functional connectivity:behaviour correlational analysis. We found that the correlated behavioural deficits summarized by the factor score were associated with correlated multi-network patterns of abnormal functional connectivity involving large swaths of cortex. Specifically, dorsal attention and sensory-motor networks showed: (i) reduced interhemispheric functional connectivity; (ii) reduced anti-correlation with fronto-parietal and default mode networks in the right hemisphere; and (iii) increased intrahemispheric connectivity with the basal ganglia. These patterns of functional connectivity:behaviour correlations were stronger in patients with right- as compared to left-hemisphere damage and were independent of lesion volume. Our findings identify large-scale changes in resting state network interactions that are a physiological signature of spatial neglect and may relate to its right hemisphere lateralization.