Aumento de los depósitos cerebrales de hierro en una familia de donantes de sangre con síndrome de piernas inquietas / Brain iron accumulation in a blood donor family with restless legs síndrome

Introducción. La fisiopatología del síndrome de piernas inquietas (SPI) es compleja. El mecanismo a través del cual la ferropenia favorece el desarrollo del SPI no está esclarecido, aunque se sugiere la presencia de una alteración en la homeostasis cerebral del hierro. Casos clínicos. Se presentan los hallazgos inusuales en una familia de donantes de sangre con SPI. Tres miembros de la misma familia fueron diagnosticados de SPI, cumpliendo los criterios definidos por el grupo internacional para el estudio del SPI (International Restless Legs Syndrome Study Group). Todos eran donantes de sangre habituales (rango de donación: 10-40 años) y los síntomas de SPI tenían un curso de 3-5 años. La exploración general y neurológica fue normal en todos los casos, así como los electromiogramas. El estudio fenotípico y genotípico descartó la presencia de hemocromatosis y otras causas genéticas de sobrecarga cerebral de hierro. Los estudios polisomnográficos mostraron sueño nocturno perturbado, con reducción de su eficiencia, y un aumento del índice de movimientos periódicos de las piernas. La resonancia magnética craneal evidenció un aumento de los depósitos cerebrales de hierro en los ganglios basales, la sustancia negra, el núcleo rojo y los dentados. Conclusión. Este aumento patológico de los depósitos cerebrales de hierro sugiere la presencia de un complejo trastorno del metabolismo cerebral del hierro en nuestros pacientes. Futuros estudios deben confirmar estos hallazgos y profundizar en el estudio de su relación con la fisiopatología del SPI

Introduction. The pathophysiology of restless legs syndrome (RLS) is complex. Secondary RLS with iron deficiency - which suggests disturbed iron homeostasis - remains to be elucidated. Case reports. We report the findings from a unique blood donor family with RLS. Three blood donors family members were diagnosed with RLS defined by the International RLS Study Group and without history of neurologic diseases and RLS symptoms in the last 3-5 years (range of blood donation: 10-40 years). The neurological examination and electromyographies were normal. A polisomnography showed disturbed nocturnal sleep with a reduction in sleep efficiency and an increased periodic limbs movement index. The cranial MRI showed brain iron deposits in basal ganglia, substantia nigra, red nuclei and dentate nuclei. Phenotypic and genotypic studies rule out genetic haemochromatosis or iron overload. Conclusion. The abnormal iron accumulation in the basal ganglia indicated a complex iron metabolism disorder of the central nervous system. Further studies are warranted to confirm our findings and its role in the pathophysiology of RLS

Apathy Due to Injury of the Prefrontocaudate Tract Following Mild Traumatic Brain Injury.

In this study, we report on a patient who developed apathy resulting from injury to the prefrontocaudate tract following mild traumatic brain injury (TBI), which was observed on diffusion tensor tractography (DTT). A 46-year-old female patient was involved in a bus accident. Her history included intracerebral hemorrhage (ICH) in the left putamen 4 years ago before the head trauma, and her family reported that she had fully recovered. She developed apathy after the TBI, worsening over time. Decreased neural connectivity of the left caudate nucleus (CN) to the left upper medial prefrontal cortex (PFC) resulting from the ICH was observed on the pre-TBI-DTT, whereas on the post-TBI-DTT (28 months after TBI), the neural connectivity of the left CN to the left upper medial PFC was increased, whereas that to the left lower medial PFC and orbitofrontal cortex was decreased. In the right hemisphere, decreased neural connectivity of the CN to the medial PFC and orbitofrontal cortex was observed on the post-TBI-DTT compared with the pre-TBI-DTT. Injury of the prefrontocaudate tract was observed in a patient with old ICH who developed apathy following mild TBI, using DTT.

Double dissociation of the anterior and posterior dorsomedial caudate-putamen in the acquisition and expression of associative learning with the nicotine stimulus.

Tobacco use is the leading cause of preventable deaths worldwide. This habit is not only debilitating to individual users but also to those around them (second-hand smoking). Nicotine is the main addictive component of tobacco products and is a moderate stimulant and a mild reinforcer. Importantly, besides its unconditional effects, nicotine also has conditioned stimulus effects that may contribute to the tenacity of the smoking habit. Because the neurobiological substrates underlying these processes are virtually unexplored, the present study investigated the functional involvement of the dorsomedial caudate putamen (dmCPu) in learning processes with nicotine as an interoceptive stimulus. Rats were trained using the discriminated goal-tracking task where nicotine injections (0.4 mg/kg; SC), on some days, were paired with intermittent (36 per session) sucrose deliveries; sucrose was not available on interspersed saline days. Pre-training excitotoxic or post-training transient lesions of anterior or posterior dmCPu were used to elucidate the role of these areas in acquisition or expression of associative learning with nicotine stimulus. Pre-training lesion of p-dmCPu inhibited acquisition while post-training lesions of p-dmCPu attenuated the expression of associative learning with the nicotine stimulus. On the other hand, post-training lesions of a-dmCPu evoked nicotine-like responding following saline treatment indicating the role of this area in disinhibition of learned motor behaviors. These results, for the first time, show functionally distinct involvement of a- and p-dmCPu in various stages of associative learning using nicotine stimulus and provide an initial account of neural plasticity underlying these learning processes.

Recovery of akinetic mutism and injured prefronto-caudate tract following shunt operation for hydrocephalus and rehabilitation: A case report.

RATIONALE: A 76-year-old female patient was diagnosed with an aneurysmal subarachnoid hemorrhage following rupture of a right posterior communicating artery aneurysm. PATIENT CONCERNS: She was treated surgically with clipping of the aneurysmal neck. Six months after onset, when starting rehabilitation at our hospital, she showed no spontaneous movement or speech. DIAGNOSES:: aneurysmal subarachnoid hemorrhage following rupture of a right posterior communicating artery aneurysm. INTERVENTIONS: During 2 months' rehabilitation, her AM did not improve significantly. As there was no apparent change, she underwent a ventriculo-peritoneal shunt operation for hydrocephalus 8 months after her stroke. After the surgery, she remained in the AM state, but participated in a comprehensive rehabilitative management program similar to that before shunt operation. During 1 month's intensive rehabilitation, her AM gradually improved. At 9 months after onset, she became able to perform some daily activities by herself including eating, washing, and dressing. In addition, she could speak with some fluency. OUTCOMES: On 6-month DTT, the neural connectivity of the caudate nucleus (CN) to the medial prefrontal cortex (PFC, Broadmann area [BA]: 10 and 12) and orbito-frontal cortex (BA 11 and 13) was low in both hemispheres. However, the neural connectivity of the CN to the medial PFC increased on both sides on 9-month DTT. The integrity of the arcuate fasciculus (AF) was preserved in both hemispheres on both 6- and 9-month DTTs. LESSONS: Recovery of AM and injured PCTs was observed in a stroke patient.

Hemorragia de núcleo caudado por anestesia dental / Caudal nucleus haemorrhage due to dental anaesthesia

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Effects of electric stimulation and destruction of caudate nucleus on short-term memory.

The effects of stimulation and destruction of the caudate nucleus on the cat short-term memory were studied by the method of classical delayed reactions. Short-term memory improved, if electrical stimulation of the caudate nucleus before presentation of the conditioned signal caused desynchronization of the electrocorticogram in the prefrontal and temporal cortex. Unilateral destruction of the caudate nucleus leading to the development of hyperactivity and attention disorders deteriorated short-term memory.

Monocyte chemoattractant protein-1 correlates with subcortical brain injury in HIV infection.

Various biomarkers have been suggested as associative or predictive of HIV-associated neurocognitive impairment. Plasma levels of monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor alpha (TNF-alpha), and hematocrit were evaluated for relationships with diffusion tensor imaging measurements of centrum semiovale, caudate, and putamen. MCP-1 levels correlated with tissue status (mean diffusivity) in all examined regions. Plasma markers were also significantly correlated with anisotropy measurements in centrum semiovale (TNF-alpha) and putamen (hematocrit).

Application of a data-mining method based on Bayesian networks to lesion-deficit analysis.

Although lesion-deficit analysis (LDA) has provided extensive information about structure-function associations in the human brain, LDA has suffered from the difficulties inherent to the analysis of spatial data, i.e., there are many more variables than subjects, and data may be difficult to model using standard distributions, such as the normal distribution. We herein describe a Bayesian method for LDA; this method is based on data-mining techniques that employ Bayesian networks to represent structure-function associations. These methods are computationally tractable, and can represent complex, nonlinear structure-function associations. When applied to the evaluation of data obtained from a study of the psychiatric sequelae of traumatic brain injury in children, this method generates a Bayesian network that demonstrates complex, nonlinear associations among lesions in the left caudate, right globus pallidus, right side of the corpus callosum, right caudate, and left thalamus, and subsequent development of attention-deficit hyperactivity disorder, confirming and extending our previous statistical analysis of these data. Furthermore, analysis of simulated data indicates that methods based on Bayesian networks may be more sensitive and specific for detecting associations among categorical variables than methods based on chi-square and Fisher exact statistics.

The effect of the destruction of the caudate-putamen on the development of amygdaloid kindling and kindled seizures.

To elucidate the possible roles of the caudate-putamen (CP) on the development of amygdala (AM) kindling and AM-kindled seizures, the bilateral CP were destroyed by intra-CP injection of ibotenic acid (0.5 or 1.0 microg per side) before the AM kindling or after completion of the AM kindling. Prior destruction of the CP, especially by 0.5 microg ibotenic acid injection, caused a significant delay in seizure development. However, after completion of the AM kindling, bilateral destruction of the CP significantly suppressed AM-kindled seizures in proportion to lesion size, however, all animals reached a stage 5 seizure by additional stimulations and established AM kindling. These findings suggest that the intact CP modulates the development of the AM kindling and the generalization and/or expression of the kindled AM seizures, and that the CP plays an important role in the generalization and/or expression of the kindled AM seizures.

Region-specific attenuation of a trypsin-like protease in substantia nigra following dopaminergic neurotoxicity by 1-methyl-4-phenyl-1,2, 3,6-tetrahydropyridine.

We analysed apoptosis, caspase-1 and -3, and trypsin-like protease activity in the nigrostriatal pathway during 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-induced neurotoxicity. MPTP injected (30 mg/kg, i.p., twice, 16 h apart) mice were sacrificed on 1, 2 and 7 days. DNA extracted from nucleus caudatus putamen (NCP) and substantia nigra (SN) was subjected to agarose gel electrophoresis. Typical apoptotic-like DNA cleavage was absent in SN or NCP after this dose of MPTP. A trypsin-like protease activity was significantly decreased in SN and not in NCP. While caspase-3 activity in the whole brain was increased significantly, caspase-1 activity was unaffected. Striatal dopamine content was decreased to 75% by 7 days. The absence of typical DNA 'ladder' when there was severe striatal dopamine depletion suggests that in vivo MPTP-mediated dopaminergic neurotoxicity may not involve apoptotic cell death, and explains why in mice MPTP-induced dopamine depletion is transient. The region-specific decrease in trypsin-like protease activity and absence of caspase-3 activation in SN signify the importance of trypsin-like protease in the regulation of apoptosis in MPTP-neurotoxicity in mice.

Is the spatial distribution of brain lesions associated with closed-head injury predictive of subsequent development of attention-deficit/hyperactivity disorder? Analysis with brain-image database.

PURPOSE: To determine whether there is an association between the spatial distribution of lesions detected at magnetic resonance (MR) imaging of the brain in children after closed-head injury and the development of secondary attention-deficit/hyperactivity disorder (ADHD). MATERIALS AND METHODS: Data obtained from 76 children without prior history of ADHD were analyzed. MR images were obtained 3 months after closed-head injury. After manual delineation of lesions, images were registered to the Talairach coordinate system. For each subject, registered images and secondary ADHD status were integrated into a brain-image database, which contains depiction (visualization) and statistical analysis software. Using this database, we assessed visually the spatial distributions of lesions and performed statistical analysis of image and clinical variables. RESULTS: Of the 76 children, 15 developed secondary ADHD. Depiction of the data suggested that children who developed secondary ADHD had more lesions in the right putamen than children who did not develop secondary ADHD; this impression was confirmed statistically. After Bonferroni correction, we could not demonstrate significant differences between secondary ADHD status and lesion burdens for the right caudate nucleus or the right globus pallidus. CONCLUSION: Closed-head injury-induced lesions in the right putamen in children are associated with subsequent development of secondary ADHD. Depiction software is useful in guiding statistical analysis of image data.

Traumatic brain injury: diffusion-weighted MR imaging findings.

BACKGROUND AND PURPOSE: Diffuse axonal injury (DAI) accounts for a significant portion of primary intra-axial lesions in cases of traumatic brain injury. The goal of this study was to use diffusion-weighted MR imaging to characterize DAI in the setting of acute and subacute traumatic brain injury. METHODS: Nine patients ranging in age from 26 to 78 years were examined with conventional MR imaging (including fast spin-echo T2-weighted, fluid-attenuated inversion-recovery, and gradient-echo sequences) as well as echo-planar diffusion-weighted MR imaging 1 to 18 days after traumatic injury. Lesions were characterized as DAI on the basis of their location and their appearance on conventional MR images. Trace apparent diffusion coefficient (ADC) maps were computed off-line with the diffusion-weighted and base-line images. Areas of increased signal were identified on the diffusion-weighted images, and regions of interests were used to obtain trace ADC values. RESULTS: In the nine patients studied, isotropic diffusion-weighted images showed areas of increased signal with correspondingly decreased ADC. In one case, decreased ADC was seen 18 days after the initial event. CONCLUSION: Decreased ADC can be demonstrated in patients with DAI in the acute setting and may persist into the subacute period, beyond that described for cytotoxic edema in ischemia.

Memory and socioemotional behavior in monkeys after hippocampal damage incurred in infancy or in adulthood.

The present study reviews the long-term effects of neonatal hippocampal damage in monkeys on the development of memory functions and socioemotional behavior. The results showed that neonatal damage to the hippocampal formation impairs specific memory processes, such as those subserving automatic (as opposed to effortful) recognition memory and relational learning, while sparing the abilities to acquire skills, such as object discriminations. Furthermore, the neonatal hippocampectomy led to a progressive loss of social affiliation and a protracted emergence of locomotor stereotypies. While the memory losses following neonatal hippocampal lesions resemble those found after similar lesions acquired in adulthood, only the neonatal lesions resulted in a protracted emergence of abnormal behaviors. These later findings suggested that, presumably, the neonatal lesions impacted on neural systems remote from the site of damage. This was confirmed by our more recent neurobiological studies, demonstrating that neonatal, but not late, lesions of the medial temporal lobe region, disrupt the normal behavioral and cognitive processes subserved by the prefrontal cortex and the caudate nucleus. All together the data support the neurodevelopmental hypothesis viewing early insult to the medial temporal region as the origin of developmental psychosis in humans, such as schizophrenia.

Infusion of glial maturation factor-beta reduces behavioral deficits after caudate nucleus injury in rats.

Adult rats with bilateral thermal lesions of the caudate nuclei (CN) show severe learning and memory deficits. The present study was designed to test the effects of an astroglial stimulating growth factor in this behavioral model. Immediately after receiving lesions of the CN, experimental subjects received an injection of one of three doses of glial maturation factor-beta (GMF-beta) directly in the lesion site. All subjects were then tested for twenty days on an active avoidance spatial alternation task. The behavioral recovery of the three groups of experimental animals was compared to that of animals having received the same brain damage and administration of a control substance (lesion controls), and to that of animals receiving a sham operation and no treatment (shams). The beneficial effects of administration were evident in the group of experimental animals receiving the lowest dose of GMF-beta. The performance of animals in this group was indistinguishable from that of the shams, and was significantly better than that of the lesion controls. The results suggest a behavioral role of GMF-beta which, in an in vitro system, is known to be a growth regulator of astroglial cells.

Afferent influences on cell death and birth during development of a cortical nucleus necessary for learned vocal behavior in zebra finches.

Forebrain nuclei that control learned vocal behavior in zebra finches are anatomically distinct and interconnected by a simple pattern of axonal pathways. In the present study, we examined afferent regulation of neuronal survival during development of the robust nucleus of the archistriatum (RA). RA projection neurons form the descending motor pathway of cortical vocal-control regions and are believed to be directly involved in vocal production.RA receives afferent inputs from two other cortical regions, the lateral magnocellular nucleus of the anterior neostriatum (lMAN) and the higher vocal center (HVC).However, because the ingrowth of HVC afferent input is delayed, lMAN projection neurons provide the majority of afferent input to RA during early vocal learning. lMAN afferent input to RA is of particular interest because lMAN is necessary for vocal learning only during a restricted period of development. By making lesions of lMAN in male zebra finches at various stages of vocal development (20-60 days of age) and in adults (>90-days old), we asked whether the survival of RA neurons depends on lMAN afferent input, and if so whether such dependence changes over the course of vocal learning. The results showed that removal of lMAN afferent input induced the loss of over 40% of RA neurons among birds in early stages of vocal development(20 days of age). However, lMAN lesions lost the ability to induce RA neuron death among birds in later stages of vocal development (40 days of age and older). These findings indicate that many RA neurons require lMAN afferent input for their survival during early vocal learning, whereas the inability of lMAN lesions to induce RA neuron death in older birds may indicate a reduced requirement for afferent input or perhaps the delayed ingrowth of HVC afferent input (at approx. 35 days of age)provides an alternate source of afferent support. Removal of lMAN afferent input also dramatically increased the incidence of mitotic figures in RA, but only among 20-day-old birds at 2 days post-lesion. The early, acute nature of the mitotic events raises the possibility that cell division in RA may be regulated by lMAN afferent input.