Good functional outcome following bilateral external capsule hemorrhage mimicking bilateral basal ganglia hemorrhage in a coma patient.

Simultaneous spontaneous bilateral external capsule hemorrhage is a rare clinical entity with extremely poor outcome. However, knowledge on the effective management of this fatal disease is limited. Herein,we described a case of a 42-year-old man with acute coma and quadriplegia as well as respiratory failure related to the disease. The patient underwent minimally invasive surgery plus local thrombolysis. Consequently, he recovered with satisfactory neurological function recovery on the 180th day of follow-up.

Could pure agraphia be the only sign of stroke? Lessons from two case reports.

Agraphia is defined as the disruption of the previously intact writing skills due to an acquired brain damage. Stroke remains the most common cause of language impairment; however, writing disorders, including agraphia, are underestimated in patients with stroke. In this regard, we report two patients presenting with pure agraphia as an early symptom of stroke. Both patients complained of at least two difficulties in visualizing letter formation beforehand, the frequent need for verbal cues, misuse of lines and margins, poorly legible signature, and writing and thinking at the same time (e.g., creative thinking and taking notes). They underwent brain magnetic resonance imaging which revealed a small lacunar infarction of the left insula and external capsule (patient 1) and a small hemorrhagic lesion in the posterior limb of the left internal capsule (patient 2). To our knowledge, this is the first report on pure agraphia as the presenting symptom of stroke. We suggest that all patients with acute agraphia, even when presenting as an isolated symptom, should be evaluated for stroke, in order to better facilitate its diagnosis and treatment.

Asymptomatic Striatocapsular slit-like Hemorrhage as a Severity Marker in Patients with Hypertensive Angiopathy.

BACKGROUND: Concomitant asymptomatic striatocapsular slit-like hemorrhage (SSH) is occasionally found in patients of spontaneous intracerebral hemorrhage (ICH), but was seldomly described in the literature. In this study, we described the clinico-radiological features of asymptomatic SSH in ICH patients with hypertensive microangiopathy. METHODS AND RESULTS: 246 patients with strictly deep or mixed deep and lobar ICH/microbleeds were included. SSH was defined as hypointense lesions involving the lateral aspect of lentiform nucleus or external capsule in slit shape (>1.5 cm) on susceptibility-weighted imaging without history of associated symptoms. Demographics and neuroimaging markers were compared between patients with SSH and those without. Patients with SSH (n=24, 10%) and without SSH had comparable age (62.0 ± 12.6 vs. 62.3 ± 13.5, p = 0.912) and vascular risk factor profiles including the diagnosis of chronic hypertension, diabetes, and dyslipidemia (all p>0.05). SSH was associated with more common lobar microbleeds (79.2% vs 48.2%, p = 0.005), lacunes (75% vs. 41.4%, p = 0.002) and higher white matter hyperintensity (WMH) volumes (24.1 [10.4-46.3] vs. 13.9 [7.0-24.8] mL, p = 0.012) on MRI, as well as more frequent left ventricular hypertrophy (LVH) (50.0% vs. 20.5%, p = 0.004) and albuminuria (41.7% vs. 19.4%, p = 0.018). In multivariable analyses, SSH remains independently associated with LVH (p = 0.017) and albuminuria (p = 0.032) after adjustment for age, sex, microbleed, lacune and WMH volume. CONCLUSIONS: Asymptomatic SSH is associated with more severe cerebral small vessel disease-related change on brain MRI, and hypertensive cardiac and renal injury, suggesting a more advanced stage of chronic hypertension.

Clinicoradiological Profile of Superficial Middle Cerebral Vein Thrombosis.

BACKGROUND: The diagnosis of isolated cortical vein thrombosis (ICVT) involving superficial middle cerebral vein (SMCV) remains challenging even in the present era of modern MRI protocols. OBJECTIVE: The purpose of this study is to review the clinical and radiological characteristics of SMCV thrombosis in our hospital. METHODS: Chart review of cases of SMCV thrombosis admitted in a tertiary care university hospital in South India during a 1-year period from September 2015 to August 2016. RESULTS: Five SMCV thrombosis patients were identified and presented with focal seizures. Neuroimaging showed edema (with or without hemorrhage) of cortex and white matter of inferior frontal gyrus, temporal pole, superior temporal gyrus, insular cortex, and external capsule. The thrombosis of SMCV was demonstrated by Spin echo T1-weighted, GRE-weighted axial, and postcontrast T1-weighted images in coronal and sagittal planes, with a slice thickness of <3 mm. Four received anticoagulation and all improved rapidly and completely. CONCLUSION: SMCV thrombosis should be considered in patients having recent onset seizures in appropriate setting based on MRI evidence of parenchymal edema and/or hemorrhage in the perisylvian region along with evidence of thrombosed vein in that region. Appropriate imaging sequences help in confirmation of diagnosis.

A fixel-based analysis of micro- and macro-structural changes to white matter following adult traumatic brain injury.

Diffusion tensor imaging is often used to assess white matter (WM) changes following traumatic brain injury (TBI), but is limited in voxels that contain multiple fibre tracts. Fixel-based analysis (FBA) addresses this limitation by using a novel method of analysing high angular resolution diffusion-weighted imaging (HARDI) data. FBA examines three aspects of each fibre tract within a voxel: tissue micro-structure (fibre density [FD]), tissue macro-structure (fibre-bundle cross section [FC]) and a combined measure of both (FD and fibre-bundle cross section [FDC]). This study used FBA to identify the location and extent of micro- and macro-structural changes in WM following TBI. A large TBI sample (Nmild = 133, Nmoderate-severe = 29) and control group (healthy and orthopaedic; N = 107) underwent magnetic resonance imaging with HARDI and completed reaction time tasks approximately 7 months after their injury (range: 98-338 days). The TBI group showed micro-structural differences (lower FD) in the corpus callosum and forceps minor, compared to controls. Subgroup analyses revealed that the mild TBI group did not differ from controls on any fixel metric, but the moderate to severe TBI group had significantly lower FD, FC and FDC in multiple WM tracts, including the corpus callosum, cerebral peduncle, internal and external capsule. The moderate to severe TBI group also had significantly slower reaction times than controls, but the mild TBI group did not. Reaction time was not related to fixel findings. Thus, the WM damage caused by moderate to severe TBI manifested as fewer axons and a reduction in the cross-sectional area of key WM tracts.

Pathogenic variants in NUBPL result in failure to assemble the matrix arm of complex I and cause a complex leukoencephalopathy with thalamic involvement.

Disorders of the white matter are genetically very heterogeneous including several genes involved in mitochondrial bioenergetics. Diagnosis of the underlying cause is aided by pattern recognition on neuroimaging and by next-generation sequencing. Recently, genetic changes in the complex I assembly factor NUBPL have been characterized by a consistent recognizable pattern of leukoencephalopathy affecting deep white matter including the corpus callosum and cerebellum. Here, we report twin boys with biallelic variants in NUBPL, an unreported c.351 G > A; p.(Met117Ile) and a previously reported pathological variant c. 693 + 1 G > A. Brain magnetic resonance imaging showed abnormal T2 hyperintense signal involving the periventricular white matter, external capsule, corpus callosum, and, prominently, the bilateral thalami. The neuroimaging pattern evolved over 18 months with marked diffuse white matter signal abnormality, volume loss, and new areas of signal abnormality in the cerebellar folia and vermis. Magnetic resonance spectroscopy showed elevated lactate. Functional studies in cultured fibroblasts confirmed pathogenicity of the genetic variants. Complex I activity of the respiratory chain was deficient spectrophotometrically and on blue native gel with in-gel activity staining. There was absent assembly and loss of proteins of the matrix arm of complex I when traced with an antibody to NDUFS2, and incomplete assembly of the membrane arm when traced with an NDUFB6 antibody. There was decreased NUBPL protein on Western blot in patient fibroblasts compared to controls. Compromised NUBPL activity impairs assembly of the matrix arm of complex I and produces a severe, rapidly-progressive leukoencephalopathy with thalamic involvement on MRI, further expanding the neuroimaging phenotype.

Tractography of the external capsule and cognition: A diffusion MRI study of cholinergic fibers.

INTRODUCTION: White matter changes (WMC) in the cholinergic tracts contribute to executive dysfunction in the context of cognitive aging. WMC in the external capsule have been associated with executive dysfunction. The objectives of this study were to: 1) Characterize the lateral cholinergic tracts (LCT) and the superior longitudinal fasciculus (SLF). 2) Evaluate the association between diffusion measures within those tracts and cognitive performance. METHODS: Neuropsychological testing and high angular resolution diffusion imaging (HARDI) of 34 healthy elderly participants was done, followed by anatomically constrained probabilistic tractography reconstruction robust to crossing fibers. The external capsule was manually segmented on a mean T1 image then merged with an atlas, allowing extraction of the LCT. Diffusion tensor imaging (DTI) and HARDI-based measures were obtained. RESULTS: Correlations between diffusion measures in the LCT and the time of completion of Stroop (left LCT radial and medial diffusivity), the Symbol Search score (right LCT apparent fiber density) and the motor part of Trail-B (left LCT axial and radial diffusivity) were observed. Correlations were also found with diffusion measures in the SLF. WMC burden was low, and no correlation was found with diffusion measures or cognitive performance. DISCUSSION: DTI and HARDI, with isolation of strategic white matter tracts for cognitive functions, represent complimentary tools to better understand the complex process of brain aging.

Microneuroanatomy of the Anterior Frontal Laser Trajectory to the Insula.

BACKGROUND: Magnetic resonance imaging-guided laser interstitial thermal therapy (LITT) is an emerging minimally invasive procedure for the treatment of deep intracranial lesions. Insular lesions are challenging to treat because of the risk of damaging important surrounding structures. The precise knowledge of the neural structures that are at risk along the trajectory and during the ablation is essential to reduce associated complications. This study aims to describe the relevant anatomy of the anterior frontal LITT trajectory to the insular region by using sectional anatomy and fiber dissection technique. METHODS: Three silicone-injected cadaveric heads were used to implant laser catheters bilaterally to the insular region by using a frameless stereotactic technique from a frontal approach. Sections were cut in both the oblique axial plane parallel to the trajectory and in the coronal plane. White matter fiber dissections were used to establish the tracts related to the laser trajectory from lateral to medial and medial to lateral. RESULTS: Supraorbital regions were selected as entry points. After crossing the frontal bone, the track intersected the inferior frontal lobe. The catheter was illustrated reaching the insular region medial to the inferior fronto-occipital fasciculus and insular cortex, and superior to the uncinate fasciculus. The uncinate fasciculus, extreme capsule, claustrum, external capsule, and putamen were traversed, preserving the major vascular structures. CONCLUSIONS: Independent of the insular area treated, an understanding of the neuroanatomy related to the anterior frontal laser trajectory is essential to improve the ability to perform LITT of this challenging region.

Electrically induced verbal perseveration: A striatal deafferentation model.

OBJECTIVE: The present study aimed to elucidate the neural correlates of the deafferentation cognitive model of verbal perseveration (VP) by analyzing the connectomics of the sites where electric stimulation elicited VP during awake left glioma surgery. METHODS: We retrospectively reviewed the anatomic sites that generated VP when electrically stimulated in a series of 21 patients operated on while awake for a left glioma. Each stimulation point was manually located on the postoperative MRI and then registered to the Montreal Neurological Institute template. Connectomics of these sites were further analyzed with Tractotron and disconnectome maps. RESULTS: VP stimulation sites were located within the white matter surrounding the posterosuperior head of the caudate nucleus, as well as within the white matter of the external capsule and the superolateral wall of the temporal horn of the ventricle. Furthermore, Tractotron and disconnectome maps revealed the connectome of these stimulation sites: the inferior fronto-occipital fasciculus, frontostriatal tract, and anterior thalamic radiations. CONCLUSION: On the basis of these results and other data, we propose the following anatomic implementation of the deafferentation cognitive model: the lexico-semantic system, comprising different areas linked together through direct cortico-cortical connections, sends information to the striatum; the striato-thalamic system acts as a tunable filter of this lexico-semantic input; and the thalamus projects back to the lexico-semantic system, amplifying the targeted response and inhibiting its competitors.

Prospective memory impairment in patients with white matter lesions.

OBJECTIVE: A vast majority of the episodic memory literature in white matter lesions (WML) had focused on "retrospective memory (RM)", little was known about prospective memory (PM) in WML patients. The aim of our study was to investigate the effect of WML patients on event-based prospective memory (EBPM) and time-based prospective memory (TBPM). In addition, our study attempted to understand the possible mechanisms of PM damage in WML patients. METHODS: A total of 42 WML patients and 40 age and education level matched healthy controls were included. EBPM (an action whenever particular words were presented) and TBPM (an action at certain times) were performed to test the involvement of PM in WML. The extent of WML within cholinergic pathways were assessed using the cholinergic pathways hyperintensities scale (CHIPS). RESULTS: A significant difference was found in the performance of Montreal Cognitive Assessment (MOCA) (21.8 ± 3.9 vs. 26.6 ± 1.7, p < 0.05) and TBPM (2.88 ± 1.21 vs. 4.27 ± 0.78, p < 0.05), but not Mini-Mental State Examination (MMSE) (26.9 ± 2.8 vs. 27.3 ± 1.2, p > 0.05) and EBPM (3.62 ± 1.25 vs.4.47 ± 1.11, p > 0.05) in WML patients compared with the healthy controls. Moreover, TBPM and MOCA scores were negatively correlated with CHIPS scores. CONCLUSIONS: WML patients were impaired in TBPM but not in EBPM, supporting that EBPM and TBPM have different neural mechanisms. Our results demonstrated that WML are involved in the TBPM probably by affecting the central cholinergic pathway.

A stable and easily reproducible model of focal white matter demyelination.

BACKGROUND: Demyelination is the end product of numerous pathological processes, and also is one of the main causes of neurological disability in Multiple sclerosis (MS). Research into the pathogenesis of MS is hampered by the conventional rodent models' inability to produce stable demyelination. NEW METHOD: Focal demyelinating lesions were stereotactically targeted to the corpus callosum with a two-point injection of lysophosphatidylcholine (LPC-2) in mice. Three groups were analyzed (n = 8, each) and water maze, sensorimotor test, and compound action potential were included in functional tests. Electron microscopy was used for morphological analyses while western blot and immunohistochemistry were included for molecular detection. RESULTS: Ten days after the LPC-2 injection, the expression of myelin basic protein (MBP) was reduced, while non-phosphorylated neurofilament (SMI-32) was increased. The amplitude of the N1 segment decreased and less well-defined myelin sheaths was found. Behavioral tests showed increased latency to escape and reduced time spent in target quadrant. Four weeks later, MBP expression still reduced, SMI-32 expression was increased, both spatial learning (D24-D27) and spatial memory (D28) were still significantly impaired in LPC-2 injection mice. COMPARISON WITH EXISTING METHOD(S): Compared with the classic single-point LPC-injection model, our studies showed that the two-point LPC-injection not only could induce demyelination in a short-term manner, but also could cause demyelination in a long-term manner with little remyelination in the mouse corpus callosum. CONCLUSIONS: We established a simple, reliable, and inexpensive model of demyelination in the corpus callosum in mice, with functional and morphological reproducibility, and good validity.

Chronic Intermittent Ethanol Exposure Modulation of Glutamatergic Neurotransmission in Rat Lateral/Basolateral Amygdala is Duration-, Input-, and Sex-Dependent.

The basolateral amygdala (BLA) controls numerous behaviors, like anxiety and reward seeking, via the activity of glutamatergic principal neurons. These BLA neurons receive excitatory inputs primarily via two major anatomical pathways - the external capsule (EC), which contains afferents from lateral cortical structures, and the stria terminalis (ST), containing synapses from more midline brain structures. Chronic intermittent ethanol (CIE) exposure/withdrawal produces distinct alterations in these pathways. Specifically, 10 days of CIE (via vapor inhalation) increases presynaptic function at ST synapses and postsynaptic function at EC synapses. Given that 10-day CIE/withdrawal also increases anxiety-like behavior, we sought to examine the development of these alterations at these inputs using an exposure time-course in both male and female rats. Specifically, using 3, 7, and 10 days CIE exposure, we found that all three durations increase anxiety-like behavior in the elevated plus maze. At BLA synapses, increased presynaptic function at ST inputs required shorter exposure durations relative to post-synaptic alterations at EC inputs in both sexes. But, synaptic alterations in females required longer ethanol exposures compared to males. These data suggest that presynaptic alteration at ST-BLA afferents is an early neuroadaptation during repeated ethanol exposures. And, the similar patterns of presynaptic-then-postsynaptic facilitation across the sexes suggest the former may be required for the latter. These cooperative interactions may contribute to the increased anxiety-like behavior that is observed following CIE-induced withdrawal and may provide novel therapeutic targets to reverse withdrawal-induced anxiety.

White Matter Microstructural Similarity and Diversity of Functional Constipation and Constipation-predominant Irritable Bowel Syndrome

BACKGROUND/AIMS: The Rome III criteria separated chronic constipation into functional constipation (FC) and constipation-predominant irritable bowel syndrome (IBS-C), but some researchers questioned the partitioning and treated both as distinct parts of a continuum. The study aims to explore the similarity and diversity of brain white matter between FC and IBS-C. METHODS: The voxel-wise analysis of the diffusion parameters was used to quantify the white matter changes of female brains in 18 FC patients and 20 IBS-C patients compared with a comparison group with 19 healthy controls by tract-based spatial statistics. The correlations between diffusive parameters and clinical symptoms were evaluated using a Pearson’s correlation. RESULTS: In comparison to healthy controls, FC patients showed a decrease of fractional anisotropy (FA) and an increase of radial diffusivity (RD) in multiple major fibers encompassing the corpus callosum (CC, P = 0.001 at peak), external capsule (P = 0.002 at peak), corona radiata (CR, P = 0.001 at peak), and superior longitudinal fasciculus (SLF, P = 0.002 at peak). In contrast, IBS-C patients showed FA and RD aberrations in the CC (P = 0.048 at peak). Moreover, the direct comparison between FC and IBS-C showed only RD differences in the CR and SLF. In addition, FA and RD in the CC were significantly associated with abdominal pain for all patients, whereas FA in CR (P = 0.016) and SLF (P = 0.040) were significantly associated with the length of time per attempt and incomplete evacuation separately for FC patients. CONCLUSION: These results may improve our understanding of the pathophysiological mechanisms underlying different types of constipation.

Individual differences in social desirability are associated with white-matter microstructure of the external capsule.

Humans tend to present themselves in a positive light to gain social approval. This behavioral trait, termed social desirability, is important for various types of social success. Surprisingly, investigation into the neural underpinnings of social desirability has been limited and focused only on interindividual differences in dopamine receptor binding. These studies revealed reduced dopamine receptor binding in the striatum of individuals who are high in trait social desirability. Interestingly, high dopamine signaling has been associated with low white-matter integrity, irrespective of social desirability. Based on these findings, we hypothesized that a positive association exists between trait social desirability and the white-matter microstructure of the external capsule, which carries fibers to the striatum from the prefrontal cortex. To test this hypothesis, we collected diffusion tensor imaging data and examined the relationship between fractional anisotropy of the external capsule and participants' social desirability-our analysis revealed a positive association. As a second exploratory step, we examined the association between social desirability and white-matter microstructure throughout the whole brain. Our whole-brain analysis revealed associations within multiple major white-matter tracts, demonstrating that socially desirable behavior relies on connectivity between distributed brain regions.

Serotonin gating of cortical and thalamic glutamate inputs onto principal neurons of the basolateral amygdala.

The basolateral amygdala (BLA) is a key site for crossmodal association of sensory stimuli and an important relay in the neural circuitry of emotion. Indeed, the BLA receives substantial glutamatergic inputs from multiple brain regions including the prefrontal cortex and thalamic nuclei. Modulation of glutamatergic transmission in the BLA regulates stress- and anxiety-related behaviors. Serotonin (5-HT) also plays an important role in regulating stress-related behavior through activation of both pre- and postsynaptic 5-HT receptors. Multiple 5-HT receptors are expressed in the BLA, where 5-HT has been reported to modulate glutamatergic transmission. However, the 5-HT receptor subtype mediating this effect is not yet clear. The aim of this study was to use patch-clamp recordings from BLA neurons in an ex vivo slice preparation to examine 1) the effect of 5-HT on extrinsic sensory inputs, and 2) to determine if any pathway specificity exists in 5-HT regulation of glutamatergic transmission. Two independent input pathways into the BLA were stimulated: the external capsule to mimic cortical input, and the internal capsule to mimic thalamic input. Bath application of 5-HT reversibly reduced the amplitude of evoked excitatory postsynaptic currents (eEPSCs) induced by stimulation of both pathways. The decrease was associated with an increase in the paired-pulse ratio and coefficient of variation of eEPSC amplitude, suggesting 5-HT acts presynaptically. Moreover, the effect of 5-HT in both pathways was mimicked by the selective 5-HT1B receptor agonist CP93129, but not by the 5-HT1A receptor agonist 8-OH DPAT. Similarly the effect of exogenous 5-HT was blocked by the 5-HT1B receptor antagonist GR55562, but not affected by the 5-HT1A receptor antagonist WAY 100635 or the 5-HT2 receptor antagonists pirenperone and MDL 100907. Together these data suggest 5-HT gates cortical and thalamic glutamatergic inputs into the BLA by activating presynaptic 5-HT1B receptors.

Anodal Transcranial Direct Current Stimulation Provokes Neuroplasticity in Repetitive Mild Traumatic Brain Injury in Rats.

Repetitive mild traumatic brain injury (rmTBI) provokes behavioral and cognitive changes. But the study about electrophysiologic findings and managements of rmTBI is limited. In this study, we investigate the effects of anodal transcranial direct current stimulation (tDCS) on rmTBI. Thirty-one Sprague Dawley rats were divided into the following groups: sham, rmTBI, and rmTBI treated by tDCS. Animals received closed head mTBI three consecutive times a day. Anodal tDCS was applied to the left motor cortex. We evaluated the motor-evoked potential (MEP) and the somatosensory-evoked potential (SEP). T2-weighted magnetic resonance imaging was performed 12 days after rmTBI. After rmTBI, the latency of MEP was prolonged and the amplitude in the right hind limb was reduced in the rmTBI group. The latency of SEP was delayed and the amplitude was decreased after rmTBI in the rmTBI group. In the tDCS group, the amplitude in both hind limbs was increased after tDCS in comparison with the values before rmTBI. Anodal tDCS after rmTBI seems to be a useful tool for promoting transient motor recovery through increasing the synchronicity of cortical firing, and it induces early recovery of consciousness. It can contribute to management of concussion in humans if further study is performed.

Fibre Dissection and Sectional Study of the Major Porcine Cerebral White Matter Tracts.

White matter anatomy is the basis for numerous applications in neurology, neurosurgery and fundamental neuroscience. Although the porcine brain is frequently used as experimental model in these fields of research, the description of its white matter is not as thorough as in the human brain or other species. Thus, the aim of this study is to describe the porcine white matter tracts in a complex manner. Two stepwise dissection protocols adapted from human anatomy were performed on six adult pig brain hemispheres prepared according to the Klingler method. Other four hemispheres were sectioned along section planes that were chosen similar to the Talairach coordinate system. As a result, three commissural tracts, seven association tracts and one projection tract were identified: corpus callosum, fornix, commissura rostralis, the short-association tracts, fasciculus longitudinalis superior, fasciculus uncinatus, fasciculus longitudinalis inferior, fasciculus occipitofrontalis inferior, cingulum, tractus mamillothalamicus and capsula interna. They were described and illustrated from multiple points of view, focusing on their trajectory, position, dimensions and anatomical relations. All in all, we achieved a three-dimensional understanding of the major tracts. The results are ready to be applied in future imagistic or experimental studies.