Posts Tagged white-matter

[ARTICLE] Impact of transcranial direct current stimulation on structural plasticity of the somatosensory system – Full Text


While there is a growing body of evidence regarding the behavioral and neurofunctional changes in response to the longitudinal delivery of transcranial direct current stimulation (tDCS), there is limited evidence regarding its structural effects. Therefore, the present study was intended to investigate the effect of repeatedly applied anodal tDCS over the primary somatosensory cortex on the gray matter (GM) and white matter (WM) compartment of the brain. Structural tDCS effects were, moreover, related to effects evidenced by functional imaging and behavioral assessment. tDCS was applied over the course of 5 days in 25 subjects with concomitant assessment of tactile acuity of the right and left index finger as well as imaging at baseline, after the last delivery of tDCS and at follow‐up 4 weeks thereafter. Irrespective of the stimulation condition (anodal vs. sham), voxel‐based morphometry revealed a behaviorally relevant decrease of GM in the precuneus co‐localized with a functional change of its activity. Moreover, there was a decrease in GM of the bilateral lingual gyrus and the right cerebellum. Diffusion tensor imaging analysis showed an increase of fractional anisotropy exclusively in the tDCSanodal condition in the left frontal cortex affecting the final stretch of a somatosensory decision making network comprising the middle and superior frontal gyrus as well as regions adjacent to the genu of the corpus callosum. Thus, this is the first study in humans to identify structural plasticity in the GM compartment and tDCS‐specific changes in the WM compartment in response to somatosensory learning.


Recently, we reported effects of repeatedly applied anodal transcranial direct current stimulation (tDCS) on tactile acuity learning of the dominant (right) index finger (IF) and concomitant neural changes as investigated by functional magnetic resonance imaging (fMRI) (Hilgenstock, Weiss, Huonker, & Witte, 2016). Relying on the same study, this article focuses on the structural underpinnings of these findings as investigated by voxel‐based morphometry (VBM) and diffusion tensor imaging (DTI).

tDCS is the application of a weak current exerting local effects on membrane potential (Bindman, 1965; Purpura & McMurtry, 1965) and neurotransmitter release (e.g., Clark, Coffman, Trumbo, & Gasparovic, 2011; Hone‐Blanchet, Edden, & Fecteau, 2016) as well as global effects on network functioning (e.g., Bachtiar, Near, Johansen‐Berg, & Stagg, 2015; Kim, Stephenson, Morris, & Jackson, 2014; Polania, Nitsche, & Paulus, 2011; Polania, Paulus, & Nitsche, 2012). Therefore, tDCS has widely been applied to study cognition, motor, and somatosensory functioning (e.g., Das, Holland, Frens, & Donchin, 2016; Stagg & Nitsche, 2011) but also to explore its beneficial potential in pathological states (e.g., Allman et al., 2016; Lindenberg, Renga, Zhu, Nair, & Schlaug, 2010; Lindenberg, Zhu, & Schlaug, 2012; Mori et al., 2013). With regard to the somatosensory system, anodal tDCS induces short‐term (e.g., Fujimoto, Yamaguchi, Otaka, Kondo, & Tanaka, 2014; Fujimoto et al., 2016; Ragert, Vandermeeren, Camus, & Cohen, 2008) as well as long‐term (Hilgenstock et al., 2016) effects on tactile acuity. After 5 days of anodal tDCS delivery, there was a profound and bilateral improvement of tactile acuity that persisted for at least 4 weeks. These improvements in tactile acuity were accompanied by changes in brain metabolism interpreted to indicate a more effective recruitment of neural machinery to process somatosensory information (Hilgenstock et al., 2016). Yet, despite the widespread application of tDCS and insights into changes in brain metabolism and connectivity, structural changes in the gray matter (GM) and white matter (WM) compartment of the brain in response to its repeated application have hardly been investigated.

Recently, Allman et al. (2016) were the first to show the capability of tDCS to induce structural changes in the GM compartment of the brain in response to repeatedly applied tDCS in stroke patients undergoing a course of 9 days of tDCS delivery with concomitant daily motor training. To the best of the authors’ knowledge, no study has investigated changes in GM in the somatosensory system in response to somatosensory training or the delivery of tDCS. Studies in the blind, however, indicate changes in GM focusing on the visual system. For example, Modi, Bhattacharya, Singh, Tripathi, and Khushu (2012) observed GM decreases in the lingual gyrus (primary visual cortex), the precuneus, the cerebellum, especially lobule VIIIa and intraparietal areas as well as an GM increase in the middle frontal gyrus (BA 6). Likewise, Voss, Pike, and Zatorre (2014) observed a significantly lower GM density in parts of the visual system and adjacent regions (pre‐/cuneus) in late blinded opposed to sighted individuals.

Changes in the WM compartment of the brain have primarily been investigated by studying fractional anisotropy (FA) (Zheng & Schlaug, 2015) that indicates organizational and directional changes in the diffusivity of water molecules in the WM compartment (Basser, 1995). Lindenberg, Nachtigall, Meinzer, Sieg, and Flöel (2013) could show that effects of tDCS on motor performance in stroke patients depended on the integrity of transcallosal and corticospinal fibers as characterized by FA (Lindenberg et al., 20122013). Moreover, Zheng and Schlaug (2015) were the first to provide evidence of a behaviorally relevant increase in FA of the so‐called alternate motor fibers (cortico‐rubro‐spinal and cortico‐reticulo‐spinal fibers) in response to repeated anodal tDCS in stroke patients. While there is no study investigating FA changes in the somatosensory domain in response to tDCS, Debowska et al. (2016) revealed changes after training of Braille reading in sighted individuals affecting the primary and secondary somatosensory system, the visual system, and the middle and superior frontal gyrus. In the blind, there is a decrease in WM in the visual system (BA 17, 18) and an increase in the superior frontal gyrus (Modi et al., 2012).

Thus, this article was intended to provide insight into where changes in tactile (acuity) perception emerge both in the GM and WM compartment of the brain (sham stimulation) and how these changes are modified by the repeated delivery of anodal tDCS. Moreover, we were interested in how somatosensory learning (sham stimulation) and its modification by anodal tDCS are implemented by combining findings from the analysis of VBM and DTI data with our previously reported findings from the analysis of fMRI and behavioral data (Hilgenstock et al., 2016). To this end, the analysis of fMRI data will be extended. Given the current state of research, we hypothesized that somatosensory learning and the repeated delivery of anodal tDCS will affect the visual system and its adjacent brain regions as well as prefrontal areas, especially the middle and superior frontal gyrus. There are only a few reports of sex‐specific tDCS‐induced effects (e.g., Chaieb, Antal, & Paulus, 2008; Fumagalli et al., 2010; Kuo, Paulus, & Nitsche, 2006). Yet, to also investigate the possibility of sex‐specific effects of tDCS in the somatosensory domain, we conducted additional exploratory analyses.[…]


Continue —> Impact of transcranial direct current stimulation on structural plasticity of the somatosensory system – Hirtz – 2018 – Journal of Neuroscience Research – Wiley Online Library

Figure 2 
(a) Significant decrease of gray matter (GM) density (red) and increase of the BOLD response (green) over the course of study projected on the MNI152 template provided by FSL, family‐wise error‐corrected on a cluster‐level at p < .05. (b) Changes in the BOLD response (green) over the course of the study and changes in relative GM volume (red) relative to baseline at the fifth day of the study (T2) and at follow‐up 4 weeks thereafter (T3) separately plotted for the sham (dark green/dark red) and anodal (light green/light red) condition (Mean ± SEM). (c) Pearson correlation between changes in relative GM volume at T3 relative to T1 and the GOT threshold (millimeter) of the right and left IF. Regression line and 95% confidence interval [Color figure can be viewed at]

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[ARTICLE] Upper Extremity Motor Impairments and Microstructural Changes in Bulbospinal Pathways in Chronic Hemiparetic Stroke – Full Text

Following hemiparetic stroke, precise, individuated control of single joints is often replaced by highly stereotyped patterns of multi-joint movement, or abnormal limb synergies, which can negatively impact functional use of the paretic arm. One hypothesis for the expression of these synergies is an increased dependence on bulbospinal pathways such as the rubrospinal (RubST) tract and especially the reticulospinal (RetST) tracts, which co-activate multiple muscles of the shoulder, elbow, wrist, and fingers. Despite indirect evidence supporting this hypothesis in humans poststroke, it still remains unclear whether it is correct. Therefore, we used high-resolution diffusion tensor imaging (DTI) to quantify white matter microstructure in relation to severity of arm synergy and hand-related motor impairments. DTI was performed on 19 moderately to severely impaired chronic stroke individuals and 15 healthy, age-matched controls. In stroke individuals, compared to controls, there was significantly decreased fractional anisotropy (FA) and significantly increased axial and radial diffusivity in bilateral corona radiata and body of the corpus callosum. Furthermore, poststroke, the contralesional (CL) RetST FA correlated significantly with both upper extremity (UE) synergy severity (r = −0.606, p = 0.003) and hand impairment (r = −0.609, p = 0.003). FA in the ipsilesional RubST significantly correlated with hand impairment severity (r = −0.590, p = 0.004). For the first time, we separately evaluate RetST and RubST microstructure in chronic stroke individuals with UE motor impairment. We demonstrate that individuals with the greatest UE synergy severity and hand impairments poststroke have the highest FA in the CL RetST a pattern consistent with increased myelination and suggestive of neuroplastic reorganization. Since the RetST pathway microstructure, in particular, is sensitive to abnormal joint coupling and hand-related motor impairment in chronic stroke, it could help test the effects of specific, and novel, anti-synergy neurorehabilitation interventions for recovery from hemiparesis.


Approximately 85% of stroke survivors experience significant motor impairment in the contralesional (CL) arm (1), which can include a loss of independent joint control (2, 3), weakness (4), and spasticity (5). After stroke, precise, individuated control of single joints is often replaced by highly stereotyped patterns of multi-joint movement caused by abnormal muscle co-activation patterns (6). The most prevalent of these patterns is the flexion synergy, which is characterized by an abnormal coupling of shoulder abduction and elbow, wrist, and finger flexion (7, 8). This impairment has a negative impact on reaching ability (9) and hand function (3, 10), both critical components of functional use of the arm during activities of daily living. Despite the debilitating nature of this motor impairment, the underlying neuropathophysiology is not fully understood.

One hypothesis for why the flexion synergy emerges is that following a reduction of corticofugal input from the lesioned hemisphere, there is an increased dependence on CL motor cortex and bulbospinal pathways, such as reticulospinal (RetST) and rubrospinal (RubST) tracts. Therefore, in the present study, we quantify microstructural properties in white matter of both the brain and the brainstem, focusing primarily on corticoreticulospinal and corticorubrospinal systems. We evaluate whether these microstructural properties increase in integrity in relation to arm synergy and hand impairment severity, which could be indicative of increased use.

Although the RetST was previously believed to be predominantly involved in gross movements, such as locomotion (11, 12) and posture (13, 14), recent work in primates suggests the RetST also influences the motor neurons that control forearm and intrinsic hand muscles (15). In the non-human primate, stimulation of the RetST produces ipsilateral wrist flexor, elbow flexor, and shoulder abductor activation (16), mirroring the flexion synergy pattern observed in humans poststroke. Furthermore, stimulating the RetST after a corticospinal tract (CST) lesion elicits increased excitatory post-synaptic potentials in motoneurons innervating the forearm flexor and intrinsic hand muscles (17). This evidence makes the contralesional corticoreticulospinal system a compelling candidate for underlying abnormal joint coupling in humans with hemiparetic stroke.

In the non-human primate, the RubST also contributes to reaching and grasping movements (18) and has been shown to be important in recovery of hand function after CST damage (19, 20). One study showed that increased white matter integrity in bilateral red nucleus (RN) correlated with worse clinical outcomes in humans with chronic stroke (21); however, the RubST has been reported as relatively insignificant in humans (22, 23). The evidence for whether the RetST and the RubST contribute to abnormal joint coupling and hand impairment in humans poststroke still remains indirect and inconclusive.

We used high-resolution diffusion tensor imaging (DTI) (24) tract-based spatial statistics (TBSS) (25) to perform a voxel-wise comparison of white matter microstructure between stroke and control individuals. We analyzed fractional anisotropy (FA), a measurement typically associated with tract integrity, as well as axial diffusivity (AD) and radial diffusivity (RD), which represent diffusion parallel and perpendicular to the principle direction of diffusion, respectively. Because previous studies have reported altered diffusion properties in lesioned tissue (2628), we excluded potential lesion-compromised voxels from our TBSS analysis to assess changes in normal-appearing white matter. We used the TBSS-derived white matter skeleton to investigate whether microstructural tissue properties within specific regions of the brainstem (CST, RetST, RubST) and subcortical white matter within CL motor areas [primary motor area (M1), premotor area (PM), supplementary motor area (SMA), body of the corpus callosum] are sensitive to upper extremity (UE) motor impairment in chronic stroke individuals.

We evaluated UE motor impairment using the Fugl-Meyer Assessment (FMA), a stroke-specific, performance-based motor impairment index, which measures impairments, such as loss of independent joint function, stretch reflex hyper-excitability, and altered sensation (29). It is one of the most widely used clinical scales of motor impairment poststroke (30). While previous studies have looked at diffusion MRI metrics in relation to the entire FMA score (31, 32), we used only the UE measurements of arm synergies and hand function to determine whether microstructural properties in specific white matter regions of interest (ROIs) were correlated.

In the present study, we hypothesized that microstructural integrity in specific regions of the extrapyramidal brainstem would be increased in chronic stroke in a manner sensitive to synergy and hand-related impairment severity. We demonstrate a significant decrease in FA in bilateral corona radiata and body of the corpus callosum in chronic stroke when compared to controls; however, within stroke subjects, specific brainstem regions show the highest FA in individuals with the most synergy-driven arm and hand impairment. More precisely, we describe the relation between CL RetST integrity and both expression of synergy and hand impairment and between ipsilesional (IL) RubST integrity and hand impairment in chronic hemiparetic stroke individuals.[…]

Continue —> Frontiers | Upper Extremity Motor Impairments and Microstructural Changes in Bulbospinal Pathways in Chronic Hemiparetic Stroke | Neurology

Figure 1. Region of interest masks in Montreal Neurological Institute’s space. (A) Primary motor area (red), supplementary motor area (green), premotor area (blue), (B) body of the corpus callosum (light blue), (C) horizontal midbrain cross-section showing cerebral peduncle (CP) portion of the corticospinal tract (yellow) and red nucleus (RN) (red), (D) horizontal pontine cross-section showing reticular formation (RF) (green), and (E) sagittal brainstem showing RF including reticulospinal (green) and RN including rubrospinal tracts (red).

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[ARTICLE] Hemispheric asymmetry in myelin after stroke is related to motor impairment and function – Full Text

Fig. 1


The relationships between impairment, function, arm use and underlying brain structure following stroke remain unclear. Although diffusion weighted imaging is useful in broadly assessing white matter structure, it has limited utility in identifying specific underlying neurobiological components, such as myelin. The purpose of the present study was to explore relationships between myelination and impairment, function and activity in individuals with chronic stroke. Assessments of paretic upper-extremity impairment and function were administered, and 72-hour accelerometer based activity monitoring was conducted on 19 individuals with chronic stroke. Participants completed a magnetic resonance imaging protocol that included a high resolution T1 anatomical scan and a multi-component T2 relaxation imaging scan to quantify myelin water fraction (MWF). MWF was automatically parcellated from pre- and post-central subcortical regions of interest and quantified as an asymmetry ratio (contralesional/ipsilesional). Cluster analysis was used to group more and less impaired individuals based on Fugl-Meyer upper extremity scores. A significantly higher precentral MWF asymmetry ratio was found in the more impaired group compared to the less impaired group (p < 0.001). There were no relationships between MWF asymmetry ratio and upper-limb use. Stepwise multiple linear regression identified precentral MWF asymmetry as the only variable to significantly predict impairment and motor function in the upper extremity (UE). These results suggest that asymmetric myelination in a motor specific brain area is a significant predictor of upper-extremity impairment and function in individuals with chronic stroke. As such, myelination may be utilized as a more specific marker of the neurobiological changes that predict long term impairment and recovery from stroke.

1. Introduction

Improved medical management of stroke has resulted in decreasing mortality rates (Grefkes and Ward, 2014). As a result, the number of individuals living with long-term disability as a result of stroke is rising (Krueger et al., 2015). Due to the heterogeneity of clinical presentation following stroke, it is imperative to identify biomarkers that may predict long-term impairment and function in order to appropriately individualize clinical rehabilitation goals and objectives (Bernhardt et al., 2016). With advances in diagnostic and prognostic tools, it is necessary to isolate modalities that can predict long-term outcomes for individuals with stroke, and to understand the underlying neurobiology that contributes to the predictive value of those measures.

Neuroimaging can be utilized to aid in the identification of biomarkers that may predict recovery status in individuals with stroke. White matter imaging is often used as a predictor of stroke recovery (Feng et al., 2015 and Stinear et al., 2012). Diffusion tensor imaging (DTI) can be performed within 10 days post stroke to quantify initial post stroke structural degeneration (Werring, 2000). Such indices have been found to strongly predict upper-extremity motor function at both 3- and 6-months post stroke (Puig et al., 2010 and Stinear et al., 2012). The combination of acute corticomotor function, derived from DTI and motor evoked potentials, using transcranial magnetic stimulation, has also been demonstrated to strongly predict recovery from upper-extremity impairment after stroke (Byblow et al., 2015). Although these modalities are predictive of long-term upper-extremity impairment, the underlying neurobiological bases driving the relationship between white matter microstructure and motor capacity remains unclear. Although relationships between white matter integrity, quantified with DTI, and motor impairment have been established after stroke, it is important to note that DTI measures are not a specific marker for myelination (Arshad et al., 2016). While DTI can grossly identify water movement, it is unable to differentiate between individual white matter substrates, which may produce the observed signal. Multiple structural features can be individually or collectively responsible for the observed changes in DTI measures, including: 1) axonal membrane status, 2) myelin sheath thickness, 3) number of intracellular neurofilaments and microtubules, and 4) axonal packing density (Alexander et al., 2007 and Beaulieu, 2002). To understand the neurobiological components contributing to the change in motor outcome observed there is a need to adopt neuroimaging techniques that can quantify these structural features.

Myelin formation has been identified as a specific target for therapeutic intervention following stroke, as recovery of axonal fibres is not complete without adequate myelination (Mifsud et al., 2014). Oligodendrocytes are responsible for initiating a cascade of events that result in the formation of myelin. Acute cerebral ischemia, such as that caused by a stroke, causes a rapid breakdown of oligodendrocytes and demyelination (Tekkök and Goldberg, 2001), which greatly limits overall axonal integrity in the lesioned area (Saab and Nave, 2016). Although animal work has underlined the importance of active myelination on motor recovery after stroke (Chida et al., 2011 and McKenzie et al., 2014), it is unclear how these findings transfer to humans.

Until recently, technical limitations prevented the imaging of myelin in vivo. Myelin water fraction (MWF) can be derived in humans non-invasively in vivo from multi-component T2-relaxation imaging (Alonso-Ortiz et al., 2014 and Prasloski et al., 2012b). Formalin-fixed human brains yield T2 distributions similar to those found in vivo, and histopathological studies show strong correlations between MWF and staining for myelin (Laule et al., 2004 and Moore et al., 2000). With the development of non-invasive imaging techniques, myelin can be quantified in the human brain (Prasloski et al., 2012b), both cross-sectionally and longitudinally (Lakhani et al., 2016) Work form the Human Connectome Project and others have identified that the primary motor and sensory regions are among the most densely myelinated and most easily delineated in the human brain, allowing for more reliable automatic identification and parcellation of myelinated regions (Glasser et al., 2016, Glasser and Van Essen, 2011 and Nieuwenhuys and Broere, 2016). In addition, myelination of corticospinal projections from these regions may vary based on the length of the tract and the size the axon. As such, quantification of corticospinal tract (CST) myelin using in vivo neuroimaging has not been validated to date (Glasser and Van Essen, 2011). Previous work from our group did not reveal a relationship between ipsi- and contralesional CST MWF, measured from the posterior limb of the internal capsule, and motor function or impairment (Borich et al., 2013). In order to limit variability arising from CST tract heterogeneity between individuals with stroke, the current study focused on the most well defined, myelinated regions of interest, located in precentral and postcentral areas.

Recent work has demonstrated that oligodendrocyte precursor cell proliferation and myelin structure are associated with motor learning in rodent models (Gibson et al., 2014 and Xiao et al., 2016). In particular, this work emphasized the possibility that functional motor activity may influence myelination of redundant neural pathways and improve conduction velocity via more efficient neural synchrony (Fields, 2015). The current study will extend previous lines of inquiry by exploring the relationship between real-world activity in the upper-extremity to myelination in humans. The ability to use the stroke-affected upper-limb in ‘everyday tasks’ is cited as a primary goal for individuals living with stroke (Barker and Brauer, 2005 and Barker et al., 2007). Monitoring upper-extremity usage after stroke using accelerometers is a low-cost, non-invasive way to measure functional activity and to quantify overall real-world activity (Hayward et al., 2015). Use of the stroke affected upper-limb correlates with long-term motor impairment as greater activity generally results in reduced impairment (Gebruers et al., 2014, Lang et al., 2007 and Shim et al., 2014). Identifying relationships between accelerometer based measures of activity and myelination will inform future investigations about the potential specificity of myelin as predictive biomarker for understanding what people can do, via measurement of impairment and function, versus what people actually do in the real-world.

Given the important relationships between white matter, activity and post-stroke impairment as well as the recent advances in imagining techniques, it is imperative to consider the contribution of myelination to post-stroke impairment, function and activity in humans. In order to identify potential differences in myelination based on the level of impairment after stroke, the current study identified ‘more impaired (M)’ and ‘less impaired (L)’ groups of participants. Therefore, the primary objective of the current investigation is to understand whether MWF in sensorimotor regions of interest is a biomarker of long term impairment, function or arm use in a population of individuals living with chronic stroke. Furthermore, we sought to identify if there were differences in MWF in sensorimotor regions of interest between individuals classified as ‘more impaired’ versus those who were ‘less impaired’.

Continue —> Hemispheric asymmetry in myelin after stroke is related to motor impairment and function

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[WEB SITE] Stanford study finds brain abnormalities in chronic fatigue patients

An imaging study by Stanford University School of Medicine investigators has found distinct differences between the brains of patients with chronic fatigue syndrome and those of healthy people.

The findings could lead to more definitive diagnoses of the syndrome and may also point to an underlying mechanism in the disease process.

It’s not uncommon for CFS patients to face several mischaracterizations of their condition, or even suspicions of hypochondria, before receiving a diagnosis of CFS. The abnormalities identified in the study, to be published Oct. 29 in Radiology, may help to resolve those ambiguities, said lead author Michael Zeineh, MD, PhD, assistant professor of radiology.

“Using a trio of sophisticated imaging methodologies, we found that CFS patients’ brains diverge from those of healthy subjects in at least three distinct ways,” Zeineh said.

CFS affects between 1 million and 4 million individuals in the United States and millions more worldwide. Coming up with a more precise number of cases is tough because it’s difficult to actually diagnose the disease. While all CFS patients share a common symptom — crushing, unremitting fatigue that persists for six months or longer — the additional symptoms can vary from one patient to the next, and they often overlap with those of other conditions.

more–>  Stanford study finds brain abnormalities in chronic fatigue patients – PsyPost.

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