Age‐related differences in autism: The case of white matter microstructure

Autism spectrum disorder (ASD) is typified as a brain connectivity disorder in which white matter abnormalities are already present early on in life. However, it is unknown if and to which extent these abnormalities are hard‐wired in (older) adults with ASD and how this interacts with age‐related white matter changes as observed in typical aging. The aim of this first cross‐sectional study in mid‐ and late‐aged adults with ASD was to characterize white matter microstructure and its relationship with age. We utilized diffusion tensor imaging with head motion control in 48 adults with ASD and 48 age‐matched controls (30–74 years), who also completed a Flanker task. Intra‐individual variability of reaction times (IIVRT) measures based on performance on the Flanker interference task were used to assess IIVRT‐white matter microstructure associations. We observed primarily higher mean and radial diffusivity in white matter microstructure in ASD, particularly in long‐range fibers, which persisted after taking head motion into account. Importantly, group‐by‐age interactions revealed higher age‐related mean and radial diffusivity in ASD, in projection and association fiber tracts. Subtle dissociations were observed in IIVRT‐white matter microstructure relations between groups, with the IIVRT‐white matter association pattern in ASD resembling observations in cognitive aging. The observed white matter microstructure differences are lending support to the structural underconnectivity hypothesis in ASD. These reductions seem to have behavioral percussions given the atypical relationship with IIVRT. Taken together, the current results may indicate different age‐related patterns of white matter microstructure in adults with ASD. Hum Brain Mapp 38:82–96, 2017. © 2016 Wiley Periodicals, Inc.     

Speed of saccade execution and inhibition associated with fractional anisotropy in distinct fronto‐frontal and fronto‐striatal white matter pathways

Fast cancellation or switching of action plans is a critical cognitive function. Rapid signal transmission is key for quickly executing and inhibiting responses, and the structural integrity of connections between brain regions plays a crucial role in signal transmission speed. In this study, we used the search‐step task, which has been used in nonhuman primates to measure dynamic alteration of saccade plans, in combination with functional and diffusion‐weighted MRI. Functional MRI results were used to identify brain regions involved in the reactive control of gaze. Probabilistic tractography was used to identify white matter pathways connecting these structures, and the integrity of these connections, as indicated by fractional anisotropy (FA), was correlated with search‐step task performance. Average FA from tracts between the right frontal eye field (FEF) and both right supplementary eye field (SEF) and the dorsal striatum were associated with faster saccade execution. Average FA of connections between the dorsal striatum and both right SEF and right inferior frontal cortex (IFC) as well as between SEF and IFC predicted the speed of inhibition. These relationships were largely behaviorally specific, despite the correlation between saccade execution and inhibition. Average FA of connections between the IFC and both SEF and the dorsal striatum specifically predicted the speed of inhibition, and connections between the FEF and SEF specifically predicted the speed of execution. In addition, these relationships were anatomically specific; correlations were observed after controlling for global FA. These data suggest that networks supporting saccade initiation and inhibition are at least partly dissociable. Hum Brain Mapp 37:2811–2822, 2016. © 2016 Wiley Periodicals, Inc .     

“Recumbent” gait: Relationship to the phenotype of “astasia‐abasia”?

Psychogenic gait disorders can present in many different ways. Among patients with a pure psychogenic gait disorder, buckling of the knee is the most common feature, followed by astasia-abasia. Here, we describe one such patient with a very unusual gait disturbance that might be regarded as a variant of astasia-abasia. The patient characteristics are described and discussed in a historical context.     

Strategic white matter injury associated with long‐term information processing speed deficits in mild traumatic brain injury

Deficits in information processing speed (IPS) are among the earliest and most prominent cognitive manifestations in mild traumatic brain injury (mTBI). We investigated the impact of white matter fiber location on IPS outcome in an individual basis assessment. A total of 112 acute mild TBI with all CT negative underwent brain DTI and blood sampling for inflammation cytokines within 7 days postinjury and 72 age‐ and sex matched healthy controls with same assessments were enrolled. IPS outcome was assessed by the trail making test at 6–12 month postinjury in mild TBI. Fractional anisotropy (FA) features were extracted using a novel lesion‐load analytical strategy to capture spatially heterogeneous white matter injuries and minimize implicit assumptions of uniform injury across diverse clinical presentations. Acute mild TBI exhibited a general pattern of increased and decreased FA in specific white matter tracts. The power of acute FA measures to identify patients developing IPS deficits with 92% accuracy and further improved to 96% accuracy by adding inflammation cytokines. The classifiers predicted individual's IPS and working memory ratings (r = .74 and .80, respectively, p < .001). The thalamo‐cortical circuits and commissural tracts projecting or connecting frontal regions became important predictors. This prognostic model was also verified by an independent replicate sample. Our findings highlighted damage to frontal interhemispheric and thalamic projection fiber tracts harboring frontal‐subcortical neuronal circuits as a predictor for processing speed performance in mild TBI.     

Assessment of variability in the shape of the motor unit action potential,the “jiggle,” at consecutive discharges

A method for quantifing shape variability, the jiggle, of motor unit potentials (MUPs) recorded with conventional EMG electrodes is presented. Amplitude variability at each point of time of the MUP was analyzed. Two new parameters are proposed: the normalized value of the consecutive amplitude differences (CAD), and the crosscorrelational coefficient of the consecutive discharges (CCC). Simulations showed that increased jitter of the constituent single fiber potentials increases the jiggle as expressed by an increase in CAD and decrease in CCC values. Even when the jitter value of each component was fixed, increased temporal dispersion increased the jiggle whereas an increased number of fibers decreased the jiggle. This new method has been applied in normal subjects, patients with chronic neurogenic diseases and patients with ALS. Jiggle was significantly increased in the ALS group, in agreement with visual observations. We believe that this method for quantifying jiggle will increase the information obtainable from routine EMG investigations. © 1994 John Wiley & Sons, Inc.     

Understanding the association between psychomotor processing speed and white matter hyperintensity: A comprehensive multi‐modality MR imaging study

Cognitive processing speed is crucial for human cognition and declines with aging. White matter hyperintensity (WMH), a common sign of WM vascular damage in the elderly, is closely related to slower psychomotor processing speed. In this study, we investigated the association between WMH and psychomotor speed changes through a comprehensive assessment of brain structural and functional features. Multi‐modal MRIs were acquired from 60 elderly adults. Psychomotor processing speeds were assessed using the Trail Making Test Part A (TMT‐A). Linear regression analyses were performed to assess the associations between TMT‐A and brain features, including WMH volumes in five cerebral regions, diffusivity parameters in the major WM tracts, regional gray matter volume, and brain activities across the whole brain. Hierarchical regression analysis was used to demonstrate the contribution of each index to slower psychomotor processing speed. Linear regression analysis demonstrated that WMH volume in the occipital lobe and fractional anisotropy of the forceps major, an occipital association tract, were associated with TMT‐A. Besides, resting‐state brain activities in the visual cortex connected to the forceps major were associated with TMT‐A. Hierarchical regression showed fractional anisotropy of the forceps major and regional brain activities were significant predictors of TMT‐A. The occurrence of WMH, combined with the disruption of passing‐through fiber integrity and altered functional activities in areas connected by this fiber, are associated with a decline of psychomotor processing speed. While the causal relationship of this WMH‐Tract‐Function‐Behavior link requires further investigation, this study enhances our understanding of these complex mechanisms.     

A novel approach with “skeletonised MTR” measures tract‐specific microstructural changes in early primary‐progressive MS

We combined tract‐based spatial statistics (TBSS) and magnetization transfer (MT) imaging to assess white matter (WM) tract‐specific short‐term changes in early primary‐progressive multiple sclerosis (PPMS) and their relationships with clinical progression. Twenty‐one PPMS patients within 5 years from onset underwent MT and diffusion tensor imaging (DTI) at baseline and after 12 months. Patients' disability was assessed. DTI data were processed to compute fractional anisotropy (FA) and to generate a common WM “skeleton,” which represents the tracts that are “common” to all subjects using TBSS. The MT ratio (MTR) was computed from MT data and co‐registered with the DTI. The skeletonization procedure derived for FA was applied to each subject's MTR image to obtain a “skeletonised” MTR map for every subject. Permutation tests were used to assess (i) changes in FA, principal diffusivities, and MTR over the follow‐up, and (ii) associations between changes in imaging parameters and changes in disability. Patients showed significant decreases in MTR over one year in the corpus callosum (CC), bilateral corticospinal tract (CST), thalamic radiations, and superior and inferior longitudinal fasciculi. These changes were located both within lesions and the normal‐appearing WM. No significant longitudinal change in skeletonised FA was found, but radial diffusivity (RD) significantly increased in several regions, including the CST bilaterally and the right inferior longitudinal fasciculus. MTR decreases, RD increases, and axial diffusivity decreases in the CC and CST correlated with a deterioration in the upper limb function. We detected tract‐specific multimodal imaging changes that reflect the accrual of microstructural damage and possibly contribute to clinical impairment in PPMS. We propose a novel methodology that can be extended to other diseases to map cross‐subject and tract‐specific changes in MTR. Hum Brain Mapp 35:723–733, 2014. © 2013 Wiley Periodicals, Inc.     

From “Time is Brain” to “Imaging is Brain”: A Paradigm Shift in the Management of Acute Ischemic Stroke

Arterial recanalization to restore the blood supply and limit the brain damage is the primary goal in the management of acute ischemic stroke (AIS). Since the publication of pivotal randomized clinical trials in 2015, endovascular thrombectomy has become part of the standard of care in selected cases of AIS from large‐vessel occlusions up to 6 hours after the onset of symptoms. However, the association between endovascular reperfusion and improved functional outcome is not strictly time dependent. Rather than on rigid time windows, candidates should be selected based on vascular and physiologic information. This approach places imaging data at the center of treatment decisions. Advances in imaging‐based management of AIS provide crucial information about vessel occlusion, infarct core, ischemic penumbra, and degree of collaterals. This information is invaluable in identifying patients who are likely to benefit from reperfusion therapies and excluding those who are unlikely to benefit or are at risk of adverse effects. The approach to reperfusion therapies continues to evolve, and imaging is acquiring a greater role in the diagnostic work‐up and treatment decisions as shown in recent clinical trials with extended time window. The 2018 American Heart Association/American Stroke Association guidelines reflect a paradigm shift in the management of AIS from “Time is Brain” to “Imaging is Brain.” This review discusses the essential role of multimodal imaging developing from recent trials on therapy for AIS.     

On lateral septum‐like characteristics of outputs from the accumbal hedonic “hotspot” of Peciña and Berridge with commentary on the transitional nature of basal forebrain “boundaries”

Peciña and Berridge (2005; J Neurosci 25:11777–11786) observed that an injection of the μ‐opioid receptor agonist DAMGO (D‐ala²‐N‐Me‐Phe⁴‐Glycol⁵‐enkephalin) into the rostrodorsal part of the accumbens shell (rdAcbSh) enhances expression of hedonic “liking” responses to the taste of an appetitive sucrose solution. Insofar as the connections of this hedonic “hotspot” were not singled out for special attention in the earlier neuroanatomical literature, we undertook to examine them. We observed that the patterns of inputs and outputs of the rdAcbSh are not qualitatively different from those of the rest of the Acb, except that outputs from the rdAcbSh to the lateral preoptic area and anterior and lateral hypothalamic areas are anomalously robust and overlap extensively with those of the lateral septum. We also detected reciprocal interconnections between the rdAcbSh and lateral septum. Whether and how these connections subserve hedonic impact remains to be learned, but these observations lead us to hypothesize that the rdAcbSh represents a basal forebrain transition area, in the sense that it is invaded by neurons of the lateral septum, or possibly transitional neuronal forms sharing properties of both structures. We note that the proposed transition zone between lateral septum and rdAcbSh would be but one of many in the basal forebrain and conclude by reiterating the longstanding argument that the transitional nature of such boundary areas has functional importance, of which the precise nature will remain elusive until the neurophysiological and neuropharmacological implications of such zones of transition are more generally acknowledged and better addressed. J. Comp. Neurol. 521:50–68, 2013. © 2012 Wiley Periodicals, Inc.     

Conduction pathways of motor evoked potentials following transcranial magnetic stimulation: A rodent study using a “Figure-8” coil

We have examined the conduction pathways of motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation, and their correlation with locomotor function in rats. MEPs were concomitantly recorded from the spinal cord (sMEPs) and the limb muscles (mMEPs) before and after various spinal tract ablations. Motor function was also examined using an inclined plane test. sMEPs were composed of four negative peaks (N1–N4) and mMEPs of high-voltage, biphasic waves. Ventral funiculus transection reduced the N1–N3 peaks and abolished mMEPs. Contrarily, dorsal funiculus transection including the pyramidal tract did not alter these MEPs. Motor performance on an inclined plane was worse after ventral funiculus transection than after other transections. These findings indicate that, in rats, the N1–N3 peaks of magnetic sMEPs conduct ventral funiculus activity, and that magnetic mMEPs mainly reflect extrapyramidal activities and are correlated with locomotor function. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:722–731, 1998.     

Grid-mapped freeze-fracture analysis of gap junctions in gray and white matter of adult rat central nervous system,with evidence for a “panglial syncytium” that is not coupled to neurons

In white matter regions of the brain and spinal cord of adult mammals, gap junctions previously were observed linking astrocytes to astrocytes, as well as to oligodendrocytes and ependymacytes. The resulting “functional syncytium” was proposed to modulate the ion fluxes that occur during electrical activity of the associated axons. Gap junctions also have been reported linking neurons with glia, and functional neuronal-glial coupling has been postulated. To investigate the glial syncytium and the neuron-to-glia coupling hypotheses, we used “grid-mapped freeze fracture,” conventional thin-section electron microscopy, and light microscope immunocytochemistry to examine and characterize neurons and glia in gray and white matter of adult rat brain and spinal cord. We have obtained quantitative evidence for the abundance and widespread distribution of gap junctions interlinking the three primary types of macroglia throughout both gray and white matter of the mammalian central nervous system (CNS), thereby extending the concept to that of a functional panglial syncytium. In contrast to previous reports, we show that of more than 400 gap junctions in which both participating cells were identified, none were between neurons and glia. Thus, neuronal coupling and glial coupling involved separate and distinct pathways. Finally, putative water channels (i.e., “square arrays”) were confirmed to be abundant and in close association with gap junctions in astrocytes and ependymacytes. Because the astrocyte “intermediaries” extend cytoplasmic conduits throughout gray and white matter of brain and spinal cord, from the ependymal layer to the pia-glial limitans, and from oligodendrocytes surrounding axons to astrocyte endfeet surrounding capillaries, the proposed panglial syncytium, with its abundance of water channels and intercellular ion channels, is optimally positioned and equipped to modulate water and ion fluxes across broad regions of the CNS. J. Comp. Neurol. 388:265–292, 1997. © 1997 Wiley-Liss, Inc.     

Comparison of two different analysis approaches for DTI free‐water corrected and uncorrected maps in the study of white matter microstructural integrity in individuals with depression

Diffusion tensor imaging (DTI) has often been used to examine white matter (WM) tract abnormalities in depressed subjects, but these studies have yielded inconsistent results, probably, due to gender composition or small sample size. In this study, we applied different analysis pipelines to a relatively large sample of individuals with depression to determine whether previous findings in depression can be replicated with these pipelines. We used a “standard” DTI algorithm and maps computed through a free‐water (FW) corrected DTI. This latter algorithm is able to identify and separate the effects of extracellular FW on DTI metrics. Additionally, skeletonized and WM voxel‐based analysis (VBA) methods were used. Using the skeletonized method, DTI maps showed lower fractional anisotropy (FA) in depressed subjects in the left brain hemisphere, including the anterior thalamic radiation (ATR L), cortical spinal tract (CST L), inferior fronto‐occipital fasciculus, inferior longitudinal fasciculus, and superior longitudinal fasciculus (SLF L). Differences in radial diffusivity (RD) were also found. For the VBA using RD, we found different results when we used FW uncorrected and corrected DTI metrics. Relative to the VBA approach, the skeletonized analysis was able to identify more clusters where WM integrity was altered in depressed individuals. Different significant correlations were found between RD and the Patient Health Questionnaire in the CST L, and SLF L. In conclusion, the skeletonized method revealed more clusters than the VBA and individuals with depression showed multiple WM abnormalities, some of which were correlated with disease severity Hum Brain Mapp 38:4690–4702, 2017. © 2017 Wiley Periodicals, Inc.     

Respiration phase‐locks to fast stimulus presentations: Implications for the interpretation of posterior midline “deactivations”

The posterior midline region (PMR)—considered a core of the default mode network—is deactivated during successful performance in different cognitive tasks. The extent of PMR‐deactivations is correlated with task‐demands and associated with successful performance in various cognitive domains. In the domain of episodic memory, functional MRI (fMRI) studies found that PMR‐deactivations reliably predict learning (successful encoding). Yet it is unclear what explains this relation. One intriguing possibility is that PMR‐deactivations are partially mediated by respiratory artifacts. There is evidence that the fMRI signal in PMR is particularly prone to respiratory artifacts, because of its large surrounding blood vessels. As respiratory fluctuations have been shown to track changes in attention, it is critical for the general interpretation of fMRI results to clarify the relation between respiratory fluctuations, cognitive performance, and fMRI signal. Here, we investigated this issue by measuring respiration during word encoding, together with a breath‐holding condition during fMRI‐scanning. Stimulus‐locked respiratory analyses showed that respiratory fluctuations predicted successful encoding via a respiratory phase‐locking mechanism. At the same time, the fMRI analyses showed that PMR‐deactivations associated with learning were reduced during breath‐holding and correlated with individual differences in the respiratory phase‐locking effect during normal breathing. A left frontal region—used as a control region—did not show these effects. These findings indicate that respiration is a critical factor in explaining the link between PMR‐deactivation and successful cognitive performance. Further research is necessary to demonstrate whether our findings are restricted to episodic memory encoding, or also extend to other cognitive domains. Hum Brain Mapp 35:4932–4943, 2014. © 2014