Postural and gait symptoms in de novo Parkinson's disease patients correlate with cholinergic white matter pathology.

INTRODUCTION: The postural instability gait difficulty motor subtype of patients with Parkinson's disease (PIGD-PD) has been associated with more severe cognitive pathology and a higher risk on dementia compared to the tremor-dominant subtype (TD-PD). Here, we investigated whether the microstructural integrity of the cholinergic projections from the nucleus basalis of Meynert (NBM) was different between these clinical subtypes. METHODS: Diffusion-weighted imaging data of 98 newly-diagnosed unmedicated PD patients (44 TD-PD and 54 PIGD-PD subjects) and 10 healthy controls, were analysed using diffusion tensor imaging, focusing on the white matter tracts associated with cholinergic projections from the NBM (NBM-WM) as the tract-of-interest. Quantitative tract-based and voxel-based analyses were performed using FA and MD as the estimates of white matter integrity. RESULTS: Voxel-based analyses indicated significantly lower FA in the frontal part of the medial and lateral NBM-WM tract of both hemispheres of PIGD-PD compared to TD-PD. Relative to healthy control, several clusters with significantly lower FA were observed in the frontolateral NBM-WM tract of both disease groups. Furthermore, significant correlations between the severity of the axial and gait impairment and NBM-WM FA and MD were found, which were partially mediated by NBM-WM state on subjects' attentional performance. CONCLUSIONS: The PIGD-PD subtype shows a loss of microstructural integrity of the NBM-WM tract, which suggests that a loss of cholinergic projections in this PD subtype already presents in de novo PD patients.

Distinct hippocampal subfield atrophy in Parkinson's disease regarding motor subtypes.

INTRODUCTION: Global hippocampal atrophy has been repeatedly reported in patients with Parkinson's disease (PD). However, there is limited literature on the differential involvement of hippocampal subfields among PD motor subtypes. This study aimed to investigate hippocampal subfield alterations in patients with PD based on their predominant symptoms. METHOD: We enrolled 31 PD patients with the tremor-dominant (TD) subtype, 27 PD patients with postural instability and gait disturbance-dominant (PIGD) subtype, and 40 healthy controls (HCs). All participants underwent high-spatial-resolution T1-weighted magnetic resonance imaging. The volume of hippocampal subfields was measured using FreeSurfer software, compared across groups, and correlated with clinical features. RESULTS: We found volumetric reductions in the hippocampal subfield in both patient subtypes compared to HCs, which were more pronounced in the PIGD subtype. The PIGD subtype had accelerated age-related alterations in the hippocampus compared to the TD subtype. Bilateral hippocampal volumes were positively associated with cognitive performance levels, but not with disease severity and duration in patients. CONCLUSIONS: Alterations in the hippocampal subfields of patients with PD differed based on their predominant symptoms. These findings are of relevance for understanding the pathophysiology of the increased risk of cognitive impairment in PIGD.

Lateralized Deficits in Motor, Sensory, and Olfactory Domains in Dementia.

BACKGROUND: There exist functional deficits in motor, sensory, and olfactory abilities in dementias. Measures of these deficits have been discussed as potential clinical markers. OBJECTIVE: We measured the deficit of motor, sensory, and olfactory functions on both the left and right body side, to study potential body lateralizations. METHODS: This IRB-approved study (N = 84) performed left/right clinical tests of gross motor (dynamometer test), sensory (Von Frey test), and olfactory (peppermint oil test) ability. The Mini-Mental Status Exam was administered to determine level of dementia; medical and laboratory data were collected. RESULTS: Sensory and olfactory deficits lateralized to the left side of the body, while motor deficits lateralized to the right side. We found clinical correlates of motor lateralization: female, depression, MMSE <15, and diabetes. While clinical correlates of sensory lateralization: use of psychotherapeutic agent, age ≥85, MMSE <15, and male. Lastly, clinical correlates of olfactory lateralization: age <85, number of medications >10, and male. CONCLUSION: These lateralized deficits in body function can act as early clinical markers for improved diagnosis and treatment. Future research should identify correlates and corresponding therapies to strengthen at-risk areas.

Sensorimotor dysfunction in a mild mouse model of cortical contusion injury without significant neuronal loss is associated with increases in inflammatory proteins with innate but not adaptive immune functions.

Traumatic brain injury is a leading cause of mortality and morbidity in the United States. Acute trauma to the brain triggers chronic secondary injury mechanisms that contribute to long-term neurological impairment. We have developed a single, unilateral contusion injury model of sensorimotor dysfunction in adult mice. By targeting a topographically defined neurological circuit with a mild impact, we are able to track sustained behavioral deficits in sensorimotor function in the absence of tissue cavitation or neuronal loss in the contused cortex of these mice. Stereological histopathology and multiplex enzyme-linked immunosorbent assay proteomic screening confirm contusion resulted in chronic gliosis and the robust expression of innate immune cytokines and monocyte attractant chemokines IL-1ß, IL-5, IL-6, TNFα, CXCL1, CXCL2, CXCL10, CCL2, and CCL3 in the contused cortex. In contrast, the expression of neuroinflammatory proteins with adaptive immune functions was not significantly modulated by injury. Our data support widespread activation of innate but not adaptive immune responses, confirming an association between sensorimotor dysfunction with innate immune activation in the absence of tissue or neuronal loss in our mice.

Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS.

Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)exp] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG)11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.

Optokinetic Analysis in Patients With Spontaneous Horizontal Gaze-Evoked Nystagmus Without Radiological Neuropathology.

Gaze-evoked nystagmus is not rare among those who have acute balance problem and may indicate a cerebellar dysfunction that is associated with a broad spectrum of disorders. The aim of this study is to analyze optokinetic response in those patients. Eleven males and 7 females (age range: 25-60, 42.5 [9.75]) with gaze-evoked nystagmus were analyzed with optokinetic test (Micromed Inc). Nystagmus was elicited by a stimulator light spot moving across the patient's visual field at a target speed of 30 degree/second. Ten age-matched healthy participants served as controls. The gain and slow-phase velocity difference in oculomotor response from left and right stimulus was compared in patients and the control participants. One-way analysis of variance test was used for multiple variance analysis of the groups. Statistical significance was set at P < .05. Slow-phase velocity of gaze-evoked nystagmus was ranging between 6 and 19 degree/second. The mean slow-phase velocity of gaze-evoked nystagmus to the right and left was 8.1 (3.81) and 6.8 (4.67) degree/second, respectively. Optokinetic gain was out of normal limits in 10 (55.5%) patients. Comparison of mean gain difference between the patients and the normal participants was statistically significant (P = .025). No statistical difference was found in mean slow-phase velocity difference in optokinetic nystagmus between control participants and patients (P > .05 [.099]). An acute-onset balance problem may be associated with dysfunction of separate populations of neurons in the brainstem and cerebellum even if there is no radiological neuropathy since gaze-evoked nystagmus is a sign of neural integrator dysfunction. Patients with gaze-evoked nystagmus and optokinetic abnormalities may have disruption of cerebellar pathways and should be followed closely.

Improved balance performance accompanied by structural plasticity in blind adults after training.

Postural control requires the sensory integration of visual, vestibular, and proprioceptive signals. In the absence of vision, either by blindfolding or in blind individuals, balance performance is typically poorer than with sight. Previous research has suggested that despite showing compensatory vestibular and proprioceptive processing during upright standing, balance performance in blind individuals is overall lower than in sighted controls with eyes open. The present study tested whether balance training, which places demands on vestibular and proprioceptive self-motion perception, improves balance performance in blind adults, and whether we find similar structural correlates in cortical and subcortical brain areas as have been reported in sighted individuals. Fourteen congenitally or late blind adults were randomly assigned to either a balance or a relaxation group and exercised twice a week for 12 weeks. Assessments prior to and after training included balance tests and the acquisition of T1-weighted MRI images. The blind balance group significantly improved in dynamic, static, and functional balance performance compared to the blind relaxation group. The balance performance improvement did not differ from that of age- and gender matched sighted adults after balance training. Cortical thickness increased in the left parahippocampus and decreased in the inferior insula bilaterally in the blind balance group compared to the blind relaxation group. Thickness decreases in the insula were related to improved static and functional balance. Gray matter volume was reduced in the left hippocampus proper and increased in the right subiculum in the blind balance group. The present data suggest that impaired balance performance in blind adults can be significantly improved by a training inducing plasticity in brain regions associated with vestibular and proprioceptive self-motion processing.

Therapeutic Potential of Wnt and Notch Signaling and Epigenetic Regulation in Mammalian Sensory Hair Cell Regeneration.

Hearing loss is one of the most prevalent sensory deficits worldwide and can result from the death of mechanosensory hair cells that transduce auditory signals in the cochlea. The mammalian cochlea lacks the capacity to regenerate these hair cells once damaged, and currently there are no biological therapies for hearing loss. Understanding the signaling pathways responsible for hair cell development can inform regenerative strategies and identify targets for treating hearing loss. The canonical Wnt and Notch pathways are critical for cochlear development; they converge on several key molecules, such as Atoh1, to regulate prosensory specification, proliferation, hair cell differentiation, and cellular organization. Much work has focused on Wnt and Notch modulation in the neonatal mouse cochlea, where they can promote hair cell regeneration. However, this regenerative response is limited in the adult cochlea and this might be attributed to age-dependent epigenetic modifications. Indeed, the epigenetic status at key gene loci undergoes dynamic changes during cochlear development, maturation, and aging. Therefore, strategies to improve regenerative success in the adult cochlea might require the modulation of Wnt, Notch, or other pathways, as well as targeted epigenetic modifications to alter the activity of key genes critical for supporting cell proliferation or transdifferentiation.

Evaluation of the cutaneous sensation of the face in patients with different clinical forms of leprosy.

BACKGROUND: Leprosy can be considered to be the most common peripheral neuropathy of infectious etiology and constitutes a public health problem. The standard routine examination for assessing sensory impairment in leprosy neuropathy basically evaluates hands, feet and eyes. However, evaluation of facial cutaneous sensation is not routinely performed. OBJECTIVES: The aim of this study was to evaluate facial cutaneous sensation in patients with different clinical forms of leprosy and compare the findings with those from healthy individuals. METHODOLOGY: 19 healthy controls and 71 leprosy patients who were being treated at a national reference center for leprosy in Brazil underwent facial sensation assessment using the Semmes-Weinstein monofilament test. This test was applied over the facial areas corresponding to the ophthalmic, maxillary and mandibular distal branches of the trigeminal nerve. RESULTS: The predominant clinical form in terms of changes to facial cutaneous sensation was lepromatous leprosy (LL), followed by the borderline-borderline (BB), and borderline-lepromatous (BL) forms, in comparison with healthy individuals. The distal branches most affected were the zygomatic (28.2%; 20/71), buccal (23.9%; 17/71) and nasal (22.5%; 16/71). There was asymmetrical sensory impairment of the face in 62.5% (20/32) of the cases. CONCLUSION: The face is just as impaired in leprosy as are the feet, hands and eyes, but facial impairment is underdiagnosed. Our evaluation on the different sensory branches and evidence of asymmetrical impairment of the face confirm the classically described pattern of leprosy neuropathy, i.e. consisting of asymmetrical and predominantly sensory peripheral neuropathy.

Periventricular White Matter Abnormalities on Diffusion Tensor Imaging of Postural Instability Gait Disorder Parkinsonism.

BACKGROUND AND PURPOSE: Postural instability gait disorder is a motor subtype of Parkinson disease associated with predominant gait dysfunction. We investigated the periventricular white matter comprising longitudinal, thalamic, and callosal fibers using diffusion tensor MR Imaging and examined clinical correlates in a cohort of patients with Parkinson disease and postural instability gait disorder and healthy controls. MATERIALS AND METHODS: All subjects underwent the Tinetti Gait and Balance Assessment and brain MR imaging. The DTI indices (fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) from ROIs dropped over the superior and inferior longitudinal fasciculi, inferior fronto-occipital fasciculus, anterior thalamic radiation, anterior and posterior limbs of the internal capsule, and the genu and body of corpus callosum were evaluated. RESULTS: Our findings showed that the superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, anterior thalamic radiation, genu of the corpus callosum, and body of the corpus callosum are more affected in postural instability gait disorder than in those with Parkinson disease or healthy controls, with more group differences among the longitudinal fibers. Only the callosal fibers differentiated the postural instability gait disorder and Parkinson disease groups. DTI measures in the superior longitudinal fasciculus, frontostriatal fibers (anterior thalamic radiation, anterior limb of the internal capsule), and genu of the corpus callosum fibers correlated with clinical gait severity. CONCLUSIONS: Findings from this case-control cohort lend further evidence to the role of extranigral pathology and, specifically, the periventricular fibers in the pathophysiology of postural instability gait disorder.

Imaging counterpart of postural instability and vertical ocular dysfunction in patients with PSP: A multimodal MRI study.

INTRODUCTION: We investigated the imaging counterpart of two functional domains (ocular motor dysfunction and postural instability) in progressive supranuclear palsy (PSP) patients classified according to the new clinical diagnostic criteria. METHODS: Forty-eight patients with probable PSP-Richardson's syndrome (PSP-RS), 30 with probable PSP-parkinsonism (PSP-P), 37 with Parkinson's disease (PD), and 38 controls were enrolled. For each functional domain, PSP patients were stratified by two certainty levels: vertical supranuclear gaze palsy (O1) and slowness of vertical saccades (O2) for ocular motor dysfunction; early unprovoked falls and tendency to fall on the pull-test for postural instability. Voxel-based morphometry (VBM), whole-brain fractional anisotropy (FA) and MR planimetric measurements were analysed and compared across patient groups. RESULTS: O1 was present in 64%, and O2 in 36% of all PSP patients. All PSP-RS patients showed early unprovoked falls. TBSS whole-brain analysis revealed that superior cerebellar peduncles (SCPs) were the only structures with significantly lower FA values in PSP-RS compared with PSP-P patients. PSP/O1 patients had lower FA values in midbrain than PSP/O2 patients. By contrast, VBM revealed no differences in grey matter volume between PSP patient groups. MR Planimetric measurements confirmed atrophy of midbrain and SCPs, in line with DTI findings. CONCLUSIONS: Our study demonstrates that SCPs were significantly more damaged in patients with PSP-RS in comparison with PSP-P patients, thus suggesting the role of SCPs in developing postural instability. Midbrain damage was less severe in O2 than in O1 patients, suggesting that the degree of vertical ocular dysfunction reflects the severity of midbrain atrophy.

A multidimensional concept for mercury neuronal and sensory toxicity in fish - From toxicokinetics and biochemistry to morphometry and behavior.

BACKGROUND: Neuronal and sensory toxicity of mercury (Hg) compounds has been largely investigated in humans/mammals with a focus on public health, while research in fish is less prolific and dispersed by different species. Well-established premises for mammals have been governing fish research, but some contradictory findings suggest that knowledge translation between these animal groups needs prudence [e.g. the relative higher neurotoxicity of methylmercury (MeHg) vs. inorganic Hg (iHg)]. Biochemical/physiological differences between the groups (e.g. higher brain regeneration in fish) may determine distinct patterns. This review undertakes the challenge of identifying sensitive cellular targets, Hg-driven biochemical/physiological vulnerabilities in fish, while discriminating specificities for Hg forms. SCOPE OF REVIEW: A functional neuroanatomical perspective was conceived, comprising: (i) Hg occurrence in the aquatic environment; (ii) toxicokinetics on central nervous system (CNS)/sensory organs; (iii) effects on neurotransmission; (iv) biochemical/physiological effects on CNS/sensory organs; (v) morpho-structural changes on CNS/sensory organs; (vi) behavioral effects. The literature was also analyzed to generate a multidimensional conceptualization translated into a Rubik's Cube where key factors/processes were proposed. MAJOR CONCLUSIONS: Hg neurosensory toxicity was unequivocally demonstrated. Some correspondence with toxicity mechanisms described for mammals (mainly at biochemical level) was identified. Although the research has been dispersed by numerous fish species, 29 key factors/processes were pinpointed. GENERAL SIGNIFICANCE: Future trends were identified and translated into 25 factors/processes to be addressed. Unveiling the neurosensory toxicity of Hg in fish has a major motivation of protecting ichtyopopulations and ecosystems, but can also provide fundamental knowledge to the field of human neurodevelopment.

Neuroanatomical correlates of sensory deficits in children with neonatal arterial ischemic stroke.

AIM: Our aim was to characterize the sensory processing outcome following neonatal arterial ischemic stroke (NAIS) and identify neuroanatomical correlates of abnormal sensory processing. METHOD: We evaluated children with NAIS longitudinally at 12 months, 18 months, and/or 30 months in areas of cognitive, motor, and language development. We gathered sensory processing data using the Sensory Profile-2 Caregiver Questionnaire. These data were analyzed against early magnetic resonance imaging using a voxel-based approach. RESULTS: Eighteen children (10 males, 8 females) with NAIS were evaluated longitudinally, of which six exhibited atypical sensory processing. Children with sensory processing deficits had lower overall developmental scores in motor, cognitive, and language domains. Neuroanatomical correlates were identified in the posterior periventricular white matter extending superiorly into the supramarginal gyrus, and inferiorly into the fusiform and inferior temporal gyri. INTERPRETATION: Our results provide new evidence that children with NAIS may experience difficulty processing sensory information, which is most likely associated with injuries in the posterior periventricular white matter, supramarginal gyrus, fusiform gyrus, and posterior thalamic radiation. WHAT THIS PAPER ADDS: Atypical sensory processing is common in children with neonatal arterial ischemic stroke (NAIS). NAIS territories in sensory areas were correlated with atypical sensory processing behaviors. Children with NAIS may benefit from early interventions targeted toward sensory processing. Future research mapping NAIS injuries using early magnetic resonance imaging may predict long-term outcomes.

CORRELACIÓN NEUROANATÓMICA DE LOS DÉFICITS SENSORIALES EN NIÑOS CON INFARTO ISQUÉMICO ARTERIAL NEONATAL: OBJETIVO: Nuestro objetivo fue caracterizar los efectos el procesamiento sensorial posterior a un ictus isquémico arterial neonatal (IIAN) e identificar la relación neuroanatómica del procesamiento sensorial anormal. MÉTODO: Evaluamos longitudinalmente a niños con IIAN a los 12, 18 y/o 30 meses en áreas de desarrollo cognitivo, motor y lingüístico. Recopilamos los datos del procesamiento sensorial usando el Perfil Sensorial. Estos datos fueron analizados contra las imágenes de resonancia magnética temprana utilizando la técnica de voxel-based morphometry. RESULTADOS: Fueron evaluados longitudinalmente 18 niños (10 varones, 8 mujeres) con IIAN, de los cuales seis mostraron un procesamiento sensorial atípico. Los niños con déficit del procesamiento sensorial tuvieron puntuaciones menores del desarrollo general en los dominios motor, cognitivo y lingüístico. La correlación neuroanatómica fue identificada en la sustancia blanca periventricular posterior extendiéndose superiormente hacia el giro supramarginal e inferiormente dentro del giro fusiforme y el giro temporal inferior. INTERPRETACIÓN: Nuestros resultados proporcionan nuevas evidencias que los niños con IIAN pueden experimentar dificultades en el procesamiento de información sensorial, que está probablemente asociado con lesiones en la sustancia blanca periventricular posterior, giro supramarginal, giro fusiforme y la radiación talámica posterior.

CORRELATOS NEUROANATÔMICOS DOS DÉFICITS SENSORIAIS EM CRIANÇAS COM ACIDENTE VASCULAR CEREBRAL ISQUÊMICO NEONATAL: OBJETIVOS: Nosso objetivo foi avaliar os resultados de processamento sensorial após acidente vascular cerebral isquêmico neonatal (AVC-IN) e identificar correlatos neuroanatômicos de processamentos sensoriais anormais. MÉTODO: Foram avaliadas crianças com AVC-IN longitudinalmente com 12 meses, 18 meses, e /ou 30 meses nas áreas do desenvolvimento cognitivo, motor e linguagem. Obtivemos os dados do processamento sensorial utilizando o Perfil Sensorial. Os dados foram analisados através de imagens de ressonância magnética precoce utilizando uma abordagem baseada em Voxel. RESULTADOS: Dezoito crianças (10 meninos e 8 meninas) com AVC-IN foram avaliadas longitudinalmente, das quais seis exibiram processamento sensorial atípico. Crianças com déficits de processamento sensorial tiveram menor pontuação total nos domínios de desempenho motor, cognitivo, e de linguagem. Correlatos neuroanatômicos foram identificados na substancia branca periventricular posterior, estendendo-se superiormente até o giro supramarginal e inferiormente até o giro fusiforme, e giro temporal inferior. INTERPRETAÇÃO: Estes resultados proporcionam novas evidencias de que crianças com AVC-I possam apresentar dificuldades de processar informações sensoriais, o que está provavelmente associado com danos ocorridos na substancia branca periventricular posterior, giro supramarginal, giro fusiforme, e projeções talâmicas posteriores.

Enhanced Sensory-Cognitive Processing by Activation of Nicotinic Acetylcholine Receptors.

Activation of nicotinic acetylcholine receptors (nAChRs) enhances sensory-cognitive function in human subjects and animal models, yet the neural mechanisms are not fully understood. This review summarizes recent studies on nicotinic regulation of neural processing in the cerebral cortex that point to potential mechanisms underlying enhanced cognitive function. Studies from our laboratory focus on nicotinic regulation of auditory cortex and implications for auditory-cognitive processing, but relevant emerging insights from multiple brain regions are discussed. Although the major contributions of the predominant nAChRs containing α7 (homomeric receptors) or α4 and ß2 (heteromeric) subunits are well recognized, recent results point to additional, potentially critical contributions from α2 subunits that are relatively sparse in cortex. Ongoing studies aim to elucidate the specific contributions to cognitive and cortical function of diverse nAChRs. IMPLICATIONS: This review highlights the therapeutic potential of activating nAChRs in the cerebral cortex to enhance cognitive function. Future work also must determine the contributions of relatively rare but important nAChR subtypes, potentially to develop more selective treatments for cognitive deficits.

Pathobiology of Christianson syndrome: Linking disrupted endosomal-lysosomal function with intellectual disability and sensory impairments.

Christianson syndrome (CS) is a recently described rare neurogenetic disorder presenting early in life with a broad range of neurological symptoms, including severe intellectual disability with nonverbal status, hyperactivity, epilepsy, and progressive ataxia due to cerebellar atrophy. CS is due to loss-of-function mutations in SLC9A6, encoding NHE6, a sodium-hydrogen exchanger involved in the regulation of early endosomal pH. Here we review what is currently known about the neuropathogenesis of CS, based on insights from experimental models, which to date have focused on mechanisms that affect the CNS, specifically the brain. In addition, parental reports of sensory disturbances in their children with CS, including an apparent insensitivity to pain, led us to explore sensory function and related neuropathology in Slc9a6 KO mice. We present new data showing sensory deficits in Slc9a6 KO mice, which had reduced behavioral responses to noxious thermal and mechanical stimuli (Hargreaves and Von Frey assays, respectively) compared to wild type (WT) littermates. Immunohistochemical and ultrastructural analysis of the spinal cord and peripheral nervous system revealed intracellular accumulation of the glycosphingolipid GM2 ganglioside in KO but not WT mice. This cellular storage phenotype was most abundant in neurons of lamina I-II of the dorsal horn, a major relay site in the processing of painful stimuli. Spinal cords of KO mice also exhibited changes in astroglial and microglial populations throughout the gray matter suggestive of a neuroinflammatory process. Our findings establish the Slc9a6 KO mouse as a relevant tool for studying the sensory deficits in CS, and highlight selective vulnerabilities in relevant cell populations that may contribute to this phenotype. How NHE6 loss of function leads to such a multifaceted neurological syndrome is still undefined, and it is likely that NHE6 is involved with many cellular processes critical to normal nervous system development and function. In addition, the sensory issues exhibited by Slc9a6 KO mice, in combination with our neuropathological findings, are consistent with NHE6 loss of function impacting the entire nervous system. Sensory dysfunction in intellectually disabled individuals is challenging to assess and may impair patient safety and quality of life. Further mechanistic studies of the neurological impairments underlying CS and other genetic intellectual disability disorders must also take into account mechanisms affecting broader nervous system function in order to understand the full range of associated disabilities.

Sensory Function and Chronic Pain in Multiple Sclerosis.

Objective: To examine whether hypoesthesia and chronic pain are related in patients with MS. Methods: Sixty-seven MS patients with pain and 80 persons without MS were included. Sensory functioning was tested by bedside neurological examination. Touch, joint position (dorsal column-medial lemniscus pathway), temperature sense, and pain (spinothalamic tract) were tested. Pain intensity was measured by the Colored Analogue Scale (CAS Intensity) and the Faces Pain Scale (FPS); pain affect was also measured by CAS Affect and Number of Words Chosen-Affective (NWC-A). Mood was assessed with the SCL-90 anxiety and depression subscales and the Beck Depression Inventory (BDI). Results: A significant negative relationship was found between pain intensity and the function of the dorsal column-medial lemniscal pathway, but not with the spinothalamic tract. Conclusion: In addition to the already known relation between hyperesthesia and pain, hypoesthesia for touch and joint position also seems to be related to chronic pain in MS patients.

A comparative study on pathological features of transgenic rat lines expressing either three or four repeat misfolded tau.

Human tauopathies represent a heterogeneous group of neurodegenerative disorders characterized by distinct clinical features, typical histopathological structures, and defined ratio(s) of three-repeat and four-repeat tau isoforms within pathological aggregates. How the optional microtubule-binding repeat of tau influences this differentiation of pathologies is understudied. We have previously generated and characterized transgenic rodent models expressing human truncated tau aa151-391 with either three (SHR24) or four microtubule-binding repeats (SHR72). Here, we compare the behavioral and neuropathological hallmarks of these two transgenic lines using a battery of tests for sensorimotor, cognitive, and neurological functions over the age range of 3.5-15 months. Progression of sensorimotor and neurological deficits was similar in both transgenic lines; however, the lifespan of transgenic line SHR72 expressing truncated four-repeat tau was markedly shorter than SHR24. Moreover, the expression of three or four-repeat tau induced distinct neurofibrillary pathology in these lines. Transgenic lines displayed different distribution of tau pathology and different type of neurofibrillary tangles. Our results suggest that three- and four-repeat isoforms of tau may display different modes of action in the diseased brain.

Altered functional connectivity differs in stroke survivors with impaired touch sensation following left and right hemisphere lesions.

One in two survivors experience impairment in touch sensation after stroke. The nature of this impairment is likely associated with changes associated with the functional somatosensory network of the brain; however few studies have examined this. In particular, the impact of lesioned hemisphere has not been investigated. We examined resting state functional connectivity in 28 stroke survivors, 14 with left hemisphere and 14 with right hemisphere lesion, and 14 healthy controls. Contra-lesional hands showed significantly decreased touch discrimination. Whole brain functional connectivity (FC) data was extracted from four seed regions, i.e. primary (S1) and secondary (S2) somatosensory cortices in both hemispheres. Whole brain FC maps and Laterality Indices (LI) were calculated for subgroups. Inter-hemispheric FC was greater in healthy controls compared to the combined stroke cohort from the left S1 seed and bilateral S2 seeds. The left lesion subgroup showed decreased FC, relative to controls, from left ipsi-lesional S1 to contra-lesional S1 and to distributed temporal, occipital and parietal regions. In comparison, the right lesion group showed decreased connectivity from contra-lesional left S1 and bilateral S2 to ipsi-lesional parietal operculum (S2), and to occipital and temporal regions. The right lesion group also showed increased intra-hemispheric FC from ipsi-lesional right S1 to inferior parietal regions compared to controls. In comparison to the left lesion group, those with right lesion showed greater intra-hemispheric connectivity from left S1 to left parietal and occipital regions and from right S1 to right angular and parietal regions. Laterality Indices were significantly greater for stroke subgroups relative to matched controls for contra-lesional S1 (left lesion group) and contra-lesional S2 (both groups). We provide evidence of altered functional connectivity within the somatosensory network, across both hemispheres, and to other networks in stroke survivors with impaired touch sensation. Hemisphere of lesion was associated with different patterns of altered functional connectivity within the somatosensory network and with related function was associated with different patterns of altered functional connectivity within the somatosensory network and with related functional networks.