Fiber-specific white matter reductions in Parkinson hallucinations and visual dysfunction.

OBJECTIVE: To investigate the microstructural and macrostructural white matter changes that accompany visual hallucinations and low visual performance in Parkinson disease, a risk factor for Parkinson dementia. METHODS: We performed fixel-based analysis, a novel technique that provides metrics of specific fiber-bundle populations within a voxel (or fixel). Diffusion MRI data were acquired from patients with Parkinson disease (n = 105, of whom 34 were low visual performers and 19 were hallucinators) and age-matched controls (n = 35). We used whole-brain fixel-based analysis to compare microstructural differences in fiber density (FD), macrostructural differences in fiber bundle cross section (FC), and the combined FD and FC (FDC) metric across all white matter fixels. We then performed a tract-of-interest analysis comparing the most sensitive FDC metric across 11 tracts within the visual system. RESULTS: Patients with Parkinson disease hallucinations exhibited macrostructural changes (reduced FC) within the splenium of the corpus callosum and the left posterior thalamic radiation compared to patients without hallucinations. While there were no significant changes in FD, we found large reductions in the combined FDC metric in Parkinson hallucinators within the splenium (>50% reduction compared to nonhallucinators). Patients with Parkinson disease and low visual performance showed widespread microstructural and macrostructural changes within the genu and splenium of the corpus callosum, bilateral posterior thalamic radiations, and left inferior fronto-occipital fasciculus. CONCLUSIONS: We demonstrate specific white matter tract degeneration affecting posterior thalamic tracts in patients with Parkinson disease with hallucinations and low visual performance, providing direct mechanistic support for attentional models of visual hallucinations.

Impaired visual search with paradoxically increased facilitation by emotional features after unilateral pulvinar damage.

Posterior thalamic pulvinar nuclei have been implicated in different aspects of spatial attention, but their exact role in humans remain unclear. Most neuropsychological studies of attention deficits after pulvinar lesion have concerned single patients or small samples. Here we examined a group of 13 patients with focal damage to posterior thalamus on a visual search task with faces, allowing us to test several hypotheses concerning pulvinar function in controlling attention to visually salient or emotionally significant stimuli. Our results identified two subgroups of thalamic patients with distinct patterns of attentional responsiveness to emotional and colour features in face targets. One group with lesions located in anterior and ventral portions of thalamus showed intact performance, with a normal facilitation of visual search for faces with emotional (fearful or happy) expressions on both side of space, similar to healthy controls. By contrast, a second group showed a slower and poorer detection of face targets, most severe for neutral faces, but with a paradoxically enhanced facilitation by both colour and emotional features. This second group had lesions centred on the pulvinar, involving mainly the dorso-medial sectors in patients showing enhanced effects of colour features, but extending to more dorso-lateral sectors in those with enhanced effects of emotional features. These findings reveal that pulvinar nuclei are not critical for orienting attention to emotionally or visually salient features, but instead provide new evidence in support of previous hypotheses suggesting an important role in controlling attention in visual scenes with distracting information.

The Responses of Neurons of the Somatosensory Cortex to Stimulation of the Posterior Thalamus (PO) in WAG/Rij Rats Genetically Predisposed to Absence Epilepsy.

In genetically predisposed WAG/Rij rats and healthy Wistar rats, we studied functioning of the paralemniscal region of the thalamo-cortical system. The responses of neurons of the somatosensory cortex to single electrical stimulation of the posterior nucleus of the thalamus were recorded in two- to three-monthold rats within the period when the epileptic activity was not developed. We revealed lower number of shortterm inhibitory responses in WAG/Rij rats as compared to Wistar rats. This may create preconditions for the spreading of spike-wave activity in the somatosensory cortex, which is an electrophysiological sign of absence epilepsy.

Cell cycle activation contributes to increased neuronal activity in the posterior thalamic nucleus and associated chronic hyperesthesia after rat spinal cord contusion.

Spinal cord injury (SCI) causes not only sensorimotor and cognitive deficits, but frequently also severe chronic pain that is difficult to treat (SCI pain). We previously showed that hyperesthesia, as well as spontaneous pain induced by electrolytic lesions in the rat spinothalamic tract, is associated with increased spontaneous and sensory-evoked activity in the posterior thalamic nucleus (PO). We have also demonstrated that rodent impact SCI increases cell cycle activation (CCA) in the injury region and that post-traumatic treatment with cyclin dependent kinase inhibitors reduces lesion volume and motor dysfunction. Here we examined whether CCA contributes to neuronal hyperexcitability of PO and hyperpathia after rat contusion SCI, as well as to microglial and astroglial activation (gliopathy) that has been implicated in delayed SCI pain. Trauma caused enhanced pain sensitivity, which developed weeks after injury and was correlated with increased PO neuronal activity. Increased CCA was found at the thoracic spinal lesion site, the lumbar dorsal horn, and the PO. Increased microglial activation and cysteine-cysteine chemokine ligand 21 expression was also observed in the PO after SCI. In vitro, neurons co-cultured with activated microglia showed up-regulation of cyclin D1 and cysteine-cysteine chemokine ligand 21 expression. In vivo, post-injury treatment with a selective cyclin dependent kinase inhibitor (CR8) significantly reduced cell cycle protein induction, microglial activation, and neuronal activity in the PO nucleus, as well as limiting chronic SCI-induced hyperpathia. These results suggest a mechanistic role for CCA in the development of SCI pain, through effects mediated in part by the PO nucleus. Moreover, cell cycle modulation may provide an effective therapeutic strategy to improve reduce both hyperpathia and motor dysfunction after SCI.

Activation and involvement of the lateral-posterior nucleus of the thalamus after a single generalized tonic-clonic seizure.

The lateral-posterior thalamic nuclei (LP) have been shown to play an important role in controlling epileptic activity. In addition, thalamic atrophy and neuronal loss have been observed in epilepsy. The objective of this study was to investigate whether lateral-posterior neuronal activation may be observed shortly after a single generalized seizure in rats submitted to the pilocarpine model of epilepsy. The results showed an increased lateral-posterior activation as soon as the seizure occurred, suggesting that neuronal loss in the thalamus is not only the consequence of chronic epilepsy.

Microstructural abnormalities of the posterior thalamic radiation and the mediodorsal thalamic nuclei in females with anorexia nervosa--a voxel based diffusion tensor imaging (DTI) study.

Gray matter abnormalities have been found in anorexia nervosa (AN) in several brain regions. However, little is known about white matter abnormalities under the condition of AN. To comprehensively assess the microstructural integrity of white matter pathways in women with anorexia nervosa, we performed voxel-based Diffusion Tensor Imaging (DTI). 21 women with AN according to DSM-IV criteria (9 of them recovered) and 20 female age-matched healthy control subjects were enrolled in the study. The patients had a mean body mass index of 17.2 kg/m(2) (controls: 19.6 kg/m(2)). High resolution T1 images (MP-RAGE) and DTI were performed on a 3 T Siemens-scanner. Images were pre-processed and analyzed using a modified protocol for DTI in SPM2. Fractional anisotropy (FA) maps were compared using t-tests (p < 0.05, corrected). Compared with controls, AN patients showed bilateral reductions of FA maps in the posterior thalamic radiation which includes the optic radiation, and the left mediodorsal thalamus. Our study is limited by the small sample size and its cross-sectional design. A longitudinal design with the same individuals assessed when acutely ill and recovered is warranted for future studies. For the first time, the findings of our DTI study identified disturbances of associational and commissural fibers in the bilateral occipitotemporal white matter. The results help narrowing the prevailing biological models of AN by suggesting that body image distortion is related to microstructural alterations of white matter tracts connecting the extrastriate visual cortex with other brain regions involved in body perception.

Changes in regional brain morphology in neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: Neuropsychiatric lupus (NPSLE) is a severe and potentially life-threatening condition, reported to occur in 25%-70% of patients with systemic lupus erythematosus (SLE). Brain imaging, especially magnetic resonance imaging, is frequently used to diagnose or exclude overt cerebral pathologies such as edema, hemorrhage, and central thrombosis. More advanced imaging techniques have been applied to demonstrate subtle changes in regional cerebral blood flow and brain structure. We investigated changes in regional gray-matter (GM) volume in SLE patients without neurological manifestations and NPSLE patients at an acute stage of the disease. METHODS: Using high-resolution structural images and voxel-based morphometry (VBM), we investigated regional GM volume in 20 NPSLE patients (within 2 weeks of the acute manifestation), 18 SLE patients without neurologic and/or psychiatric manifestations, and 18 healthy controls. RESULTS: VBM analyses revealed several regions of GM atrophy in various parts of the brain in NPSLE and SLE patients. GM atrophy was seen in both groups in the temporal and parietal lobes and was most pronounced in the posterior thalamus bilaterally. Both groups showed an increase in regional GM volume in the posterior parahippocampal gyrus. CONCLUSION: Our data suggest that changes in regional brain morphology are present in acute NPSLE, but also in SLE (as compared to controls), which might be indicative of a subclinical neurodegenerative process. Further research is needed to investigate whether specific neuropsychiatric symptoms are related to these changes.

Neuronal MCP-1 mediates microglia recruitment and neurodegeneration induced by the mild impairment of oxidative metabolism.

Chemokines are implicated in the neuroinflammation of several chronic neurodegenerative disorders. However, the precise role of chemokines in neurodegeneration is unknown. Thiamine deficiency (TD) causes abnormal oxidative metabolism in the brain as well as a well-defined microglia activation and neurodegeneration in the submedial thalamus nucleus (SmTN), which are common features of neurodegenerative diseases. We evaluated the role of chemokines in neurodegeneration and the underlying mechanism in a TD model. Among the chemokines examined, TD selectively induced neuronal expression of monocyte chemoattractant protein-1 (MCP-1) in the SmTN prior to microglia activation and neurodegeneration. The conditioned medium collected from TD-induced neurons caused microglia activation. With a neuron/microglia co-culture system, we showed that MCP-1-induced neurotoxicity required the presence of microglia, and exogenous MCP-1 was able to activate microglia and stimulated microglia to produce cytokines. A MCP-1 neutralizing antibody inhibited MCP-1-induced microglia activation and neuronal death in culture and in the thalamus. MCP-1 knockout mice were resistant to TD-induced neuronal death in SmTN. TD selectively induced the accumulation of reactive oxygen species in neurons, and antioxidants blocked TD-induced MCP-1 expression. Together, our results indicated an induction of neuronal MCP-1 during mild impairment of oxidative metabolism caused by microglia recruitment/activation, which exacerbated neurodegeneration.

Changes in inflammatory processes associated with selective vulnerability following mild impairment of oxidative metabolism.

Abnormalities in oxidative metabolism and reductions of thiamine-dependent enzymes accompany many age-related neurodegenerative diseases. Thiamine deficiency (TD) produces a cascade of events including mild impairment of oxidative metabolism, activation of microglia, astrocytes and endothelial cells that leads to neuronal loss in select brain regions. The earliest changes occur in a small, well-defined brain region, the submedial thalamic nucleus (SmTN). In the present study, a micropunch technique was used to evaluate quantitatively the selective regional changes in mRNA and protein levels. To test whether this method can distinguish between changes in vulnerable and non-vulnerable regions, markers for neuronal loss (NeuN) and endothelial cells (eNOS) and inflammation (IL-1beta, IL-6 and TNF-alpha) in SmTN and cortex of control and TD mice were assessed. TD significantly reduced NeuN and increased CD11b, GFAP and ICAM-1 immunoreactivity in SmTN as revealed by immunocytochemistry. When assessed on samples obtained by the micropunch method, NeuN protein declined (-49%), while increased mRNA levels were observed for eNOS (3.7-fold), IL-1beta (43-fold), IL-6 (44-fold) and TNF-alpha (64-fold) in SmTN with TD. The only TD-induced change that occurred in cortex with TD was an increase in TNF-alpha (22-fold) mRNA levels. Immunocytochemical analysis revealed that IL-1beta, IL-6 and TNF-alpha protein levels increased in TD brains and colocalized with glial markers. The consistency of these quantitative results with immunocytochemical measurements validates the micropunch technique. The results demonstrate that TD induces quantitative, distinct inflammatory responses and oxidative stress in vulnerable and non-vulnerable regions that may underlie selective vulnerability.

Posterior thalamic hemorrhage induces "pusher syndrome".

BACKGROUND: Recent findings argue for a pathway in humans for sensing the orientation of gravity and controlling upright body posture, separate from the one for orientation perception of the visual world. Stroke patients with contraversive pushing were shown to experience their body as oriented upright when actually tilted about 20 degrees to the ipsilesional side, in spite of normal visual-vestibular functioning. A recent study suggested the involvement of posterolateral thalamus typically associated with the disorder. OBJECTIVE: To evaluate the relationship between pushing behavior and thalamic function. METHODS: Over a 3-year period the authors prospectively investigated 40 patients with left- or right-sided thalamic strokes. RESULTS: Twenty-eight percent showed contraversive pushing. The authors found a strong relationship between etiology, vascular territory, lesion size, and neurologic disorders associated with contraversive pushing. Pusher patients had larger lesions that typically were caused by hemorrhage (vs infarcts) located in the posterior thalamus (vs anterior thalamic lesions in those patients without pushing behavior). A paresis of the contralesional extremities was more frequent and more severe in pusher patients. Further, these patients showed more additional spatial neglect with right thalamic lesions, while they tended to be more aphasic with left thalamic lesions. CONCLUSIONS: Posterior thalamus seems to be fundamentally involved in our control of upright body posture. Higher pressure, swelling, and other secondary pathologic processes associated with posterior thalamic hemorrhage (vs thalamic infarction) may provoke contraversive pushing in combination with additional neurologic symptoms.

Thalamic reductions in children with chromosome 22q11.2 deletion syndrome.

Children with chromosome 22q11.2 deletion syndrome (22q) suffer from physical and behavioral dysfunctions, including neuroanatomical anomalies, visuo-spatial processing deficits, and increased risk for psychopathology. Reduced total brain volume, parietal lobe volume, and cerebellar volumes, enlarged ventricles, and increased basal ganglia volumes have been reported. Since previous literature has related the pulvinar nucleus of the thalamus to visuo-spatial processing, we compared the thalamic volume in children with 22q to typically developing controls. Children with 22q showed a significant reduction of the thalamus compared with normally developing children, specifically in the posterior portion of the thalamus, including the pulvinar nucleus. These results provide the first evidence for a potential relationship between posterior thalamic reductions and the characteristic visuo-spatial deficits demonstrated in this group.

MR demonstration of partial lesions of the lateral geniculate body and its functional intra-nuclear topography.

Two rare cases with a partial lesion of the lateral geniculate body (LGB) presumably due to ischemia are demonstrated on high resolution MR imaging. A 62-year-old woman (case 1) presented with left homonymous superior quadrantanopia on Goldmann perimetry. Heavily T2 weighted MR images showed a localized lesion at the lateral portion of the LGB. The visual field defect was macular and horizontal meridian sparing and persisted for 9 years. A 49-year-old woman (case 2) presented with a sudden onset of left homonymous horizontal sectoranopia on Humphrey automated perimetry and heavily T2 weighted images demonstrated a lesion localized at the more medial part of the right LGB. Axons originating from inferior, central and superior retina are essentially located laterally, centrally and medially, respectively, in the LGB, based on the electrophysiological studies of animal experiments and this observation has been applied to humans. This study radiologically shows that a discrete lateral lesion of the LGB produced homonymous upper quadrantanopia in case 1, whereas a more medially located lesion produced homonymous sectoranopia in case 2, and reveals that the axons originating from inferior retina are located more laterally than those from central retina in the human LGB.

The ventral lateral posterior nucleus of the thalamus in schizophrenia: a post-mortem study.

The ventral lateral posterior thalamic nucleus (VLp) is an integral part of both the cerebello-thalamocortical and the basal ganglia-thalamocortical circuit. Although both circuits are thought to be involved in the pathophysiology of schizophrenia, the VLp has not yet been examined in schizophrenia. Using stereological techniques in the brains of eight patients with schizophrenia and in eight age- and sex-matched controls, we measured the nuclear volume of the VLp and obtained estimates of the total number of neurons in this nucleus. Whole brain volume did not differ between the schizophrenia group and the control group and was not correlated to the volume of the right VLp or left VLp. The volume (minus sign25%) and the total neuron number (minus sign27%) of the left VLp were significantly reduced in the schizophrenia group. There were no significant differences in the nuclear volume, neuron density and total neuron number in the right VLp between the schizophrenia group and the control group. There were no significant correlations between length of illness and the nuclear volume, neuron density and total neuron number of the left and right VLp. The present results suggest that the total neuron number of the left VLp is reduced in the schizophrenia group, which may reflect disturbed cerebello-thalamocortical and basal ganglia-thalamocortical circuits in this disease.

Intracortical inhibition is reduced in a patient with a lesion in the posterolateral thalamus.

We describe a patient who developed a complex movement disorder following an ischemic lesion in the right posterolateral thalamus. Transcranial magnetic stimulation showed a shortening of the cortical silent period and deficient cortico-cortical inhibition using paired magnetic pulses on the affected side, indicating reduced effectiveness of intracortical inhibitory mechanisms.

Imaging cortical association tracts in the human brain using diffusion-tensor-based axonal tracking.

Diffusion-tensor fiber tracking was used to identify the cores of several long-association fibers, including the anterior (ATR) and posterior (PTR) thalamic radiations, and the uncinate (UNC), superior longitudinal (SLF), inferior longitudinal (ILF), and inferior fronto-occipital (IFO) fasciculi. Tracking results were compared to existing anatomical knowledge, and showed good qualitative agreement. Guidelines were developed to reproducibly track these fibers in vivo. The interindividual variability of these reconstructions was assessed in a common spatial reference frame (Talairach space) using probabilistic mapping. As a first illustration of this technical capability, a reduction in brain connectivity in a patient with a childhood neurodegenerative disease (X-linked adrenoleukodystrophy) was demonstrated.

Component perimetry: a fast method to detect visual field defects caused by brain lesions.

PURPOSE: Noise field campimetry, performed according to Aulhorn and Köst, confronts patients with a large field of irregularly flickering dots, and many patients immediately perceive their visual field defects. The original method had a somewhat low specificity and sensitivity, especially for patients with visual field defects caused by cortical lesions. METHODS: The method was improved in two ways. First, the grain of the visual noise was increased toward the periphery of the visual field to accommodate the peripheral decrease in visual acuity. Second, the type of stimulus pattern was varied to include separate investigations of different visual components or functions (color, motion, temporal resolution, line orientation, stereoscopic depth, acuity, and figure-ground segmentation). To evaluate the reliability of the method, the visual fields were compared, as assessed by the new method, with those of conventional perimetry in 41 patients with neurologic disorders and 22 normal control subjects. RESULTS: The results were encouraging. All patients with suprageniculate lesions subjectively experienced visual field defects in component perimetry. Sizes of visual field defects obtained with both methods corresponded qualitatively with each other, with a highly significant correlation. The specificity of component perimetry was higher than that of the original noise field campimetry. CONCLUSIONS: This pilot study indicates that component perimetry is a subjective but relatively reliable method for detecting disorders of visual perception caused by lesions at different stages along the visual pathway, permitting fast screening of the visual field. In addition, this method seems to allow examination of the visual field, not only for defects in contrast sensitivity, as does conventional light perimetry, but also for the status of other components of vision such as color or motion perception. Further evaluation with larger patient cohorts is needed to allow exact assessment of the clinical usefulness of the method.