A comprehensive clinical and genetic study of a large Mexican population with spinocerebellar ataxia type 7.

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disorder characterized by progressive cerebellar ataxia associated with macular degeneration. We recently described one of the largest series of patients with SCA7 that originated from a founder effect in a Mexican population, which allowed us to perform herein the first comprehensive clinical, neurophysiological, and genetic characterization of Mexican patients with SCA7. In this study, 50 patients, categorized into adult or early phenotype, were clinically assessed using standard neurological exams and genotyped using fluorescent PCR and capillary electrophoresis. Patients with SCA7 exhibited the classical phenotype of the disease characterized by cerebellar ataxia and visual loss; however, we reported, for the first time, frontal-executive disorders and altered sensory-motor peripheral neuropathy in these patients. Semiquantitative analysis of ataxia-associated symptoms was performed using Scale for the Assessment and Rating of Ataxia (SARA) and the Brief Ataxia Rating Scale (BARS) scores, while extracerebellar features were measured employing the Inventory of Non-ataxia Symptoms (INAS) scale. Ataxia rating scales confirmed the critical role size of cytosine-adenine-guanine (CAG) repeat size on age at onset and disease severity, while analysis of CAG repeat instability showed that paternal rather than maternal transmission led to greater instability.

Analysis of CAG repeats in five SCA loci in Mexican population: epidemiological evidence of a SCA7 founder effect.

Spinocerebellar ataxias (SCA) are a heterogeneous group of neurodegenerative disorders. CAG (cytosine-adenine-guanine) trinucleotide repeat expansions in the causative genes have been identified as the cause of different SCA. In this study, we simultaneously genotyped SCA1, SCA2, SCA3, SCA6, and SCA7 applying a fluorescent multiplex polymerase chain reaction assay. We analyzed 10 families with SCA (64 patients) from five different communities of Veracruz, a Mexican southeastern state, and identified 55 patients for SCA7 and 9 for SCA2, but none for SCA1, SCA3, or SCA6. To our knowledge, this sample represents one of the largest series of SCA7 cases reported worldwide. Genotyping of 300 healthy individuals from Mexican population and compiled data from different ethnicities showed discordant results concerning the hypothesis that SCA disease alleles arise by expansion of large normal alleles.

Piracetam-induced changes on the brainstem auditory response in anesthetized juvenile rhesus monkeys (Macaca mulatta). Report of two clinical cases.

BACKGROUND: We describe two clinical cases and examine the effects of piracetam on the brainstem auditory response in infantile female rhesus monkeys (Macaca mulatta). RESULTS: We found that the interwave intervals show a greater reduction in a 3-year-old rhesus monkey compared to a 1-year-old rhesus monkey. DISCUSSION: In this report, we discuss the significance of these observations.

The selective inhibition of the D1 dopamine receptor results in an increase of metabolized dopamine in the rat striatum.

Our aim was to study the specific role of the postsynaptic D(1) receptors on dopaminergic response and analyze the metabolized dopamine (DA) in the rat striatum. We used male Wistar rats to evaluate the effects of different doses of a D(1) agonist (SKF-38393) and a D(1) antagonist (SCH-23390), and their co-administration. The levels of DA and L-3, 4-dihydroxyphenylacetic acid (DOPAC) were measured using high performance liquid chromatography. The systemic injection of SKF-38393 alone at 1, 5 and 10 mg/kg did not alter the DA and DOPAC levels or the DOPAC/DA ratio. In contrast, injection of SCH-23390 alone at 0.25, 0.5 and 1 mg/kg significantly increased the DA and DOPAC levels, as well as the DOPAC/DA ratio, compared with the respective control groups. The co-administration of SCH-23390+SKF-38393 did not alter the DA or DOPAC levels, but it did significantly inhibit the SCH-23390-induced increase of the DA and DOPAC levels. The SCH-23390+SKF-38393 and the SCH-23390-only groups showed an increase in the DOPAC/DA ratio. The co-administration of SCH-23390+PARGYLINE significantly decreased the DOPAC levels and the DOPAC/DA ratio compared with the control and SCH-23390 groups. Taken together, our results showed that selective inhibition with SCH-23390 produced an increase in metabolized DA via striatal monoamine oxidase. These findings also contribute to the understanding of the role of postsynaptic D(1) receptors in the long-loop negative feedback system in the rat striatum.

[Paradigm of negative feedback via long-loop in the striatal dopamine release modulation in the rat]. / Paradigma de retroalimentacion negativa via circuito largo en la modulacion de la liberacion de dopamina en el estriado dorsal de la rata.

INTRODUCTION: The basal ganglia include the striatum, globus pallidus, the substantia nigra pars compacta and pars reticulata. The striatum receives afferent input from the substantia nigra pars compacta. The principal neurons of the striatum are medium spiny neurons, that express high levels of D1 and D2 receptors. AIMS: This review deals about the aspects underlying to the negative feedback via long-loop in the striatal dopamine release modulation in the rat. Also, the motor function in dopamine receptor knock-out mice is discussed. DEVELOPMENT AND CONCLUSIONS: The intrastriatal infusion and systemic injection of dopamine receptor agonists and antagonists may regulate the striatal dopamine release and induce changes in motor function. Disruption of the D1 and D2 gene shown that the motor function is controlled by D1 and D2 receptors. The study of the long-loop negative feedback may contribute to our understanding in the physiology and dysfunction of basal ganglia.

Paradigma de retroalimentación negativa vía circuito largo en la modulación de la liberación de dopamina en el estriado dorsal de la rata / Paradigm of negative feedback via long-loop in the striatal dopamine release modulation in the rat

Introducción. El estriado, el globo pálido, la sustancia negra pars compacta y la sustancia negra pars reticulata integran los ganglios basales. El estriado recibe aferencias provenientes de la sustancia negra pars compacta. Las neuronas principales del estriado son las neuronas espinosas de tamaño mediano, que expresan altos niveles de receptores pertenecientes a la familia D1 (RD1) y D2 (RD2). Objetivos. Revisar el paradigma de retroalimentación negativa vía circuito largo en la modulación de la liberación de dopamina en el estriado dorsal de la rata. Además, se discute el efecto de la función motora en ratones deficientes (knockout) de receptores dopaminérgicos. Desarrollo y conclusiones. La infusión local y la inyección sistémica de fármacos agonistas y antagonistas dopaminérgicos modulan la liberación de dopamina estriatal e inducen cambios en la función motora. En ratones deficientes de RD1 o RD2 se ha demostrado que la función motora es dependiente de la integridad del sistema dopaminérgico. El estudio del paradigma de retroalimentación negativa vía circuito largo en la modulación de la liberación de dopamina permitirá comprender el funcionamiento del circuito de los ganglios basales en condiciones fisiológicas y patológicas (AU)

Introduction. The basal ganglia include the striatum, globus pallidus, the substantia nigra pars compacta and pars reticulata. The striatum receives afferent input from the substantia nigra pars compacta. The principal neurons of the striatum are medium spiny neurons, that express high levels of D1 and D2 receptors. Aims. This review deals about the aspects underlying to the negative feedback via long-loop in the striatal dopamine release modulation in the rat. Also, the motor function in dopamine receptor knock-out mice is discussed. Development and conclusions. The intrastriatal infusion and systemic injection of dopamine receptor agonists and antagonists may regulate the striatal dopamine release and induce changes in motor function. Disruption of the D1 and D2 gene shown that the motor function is controled by D1 and D2 receptors. The study of the long-loop negative feedback may contribute to our understanding in the physiology and dysfunction of basal ganglia (AU)

[Is cochlear processing involved in language disorders?]. / El procesamiento coclear está involucrado en los problemas de lenguaje?

INTRODUCTION: Otoacoustic emissions are evidence of the existence of an active process in the cochlea, and the motility of the outer hair cells means that they can change the cochlear mechanical response. We believe that incorrect processing of the sounds of language in the cochlea can result in impaired language processes. SUBJECTS AND METHODS: Data were collected from the patient record; neurological, visual and auditory examination; Weschler intelligence scale; initial language test (ILT); brainstem auditory evoked potentials (BAEPs) and transient otoacoustic emissions. The results of the ILT were used to form three groups: controls, pathological and pathological with normal ILT. RESULTS: All the children presented a response at 20 dB by means of the BAEPs. In the transient otoacoustic emissions, Student's t test was conducted between the right and the left ear for total reproducibility and reproducibility at different band frequencies within each group. No significant differences were observed. The same test was carried out between groups (controls versus pathological, controls versus pathological with normal ILT, and pathological versus pathological with normal ILT) in the right and left ears; no significant differences were found in the total reproducibility for the two ears. No significant differences were found in the reproducibility at different frequency bands for the left ear, but some were found in the case of the right ear. CONCLUSIONS: Laterality from the periphery exists for language processing and if this process fails to perform correctly, due to malfunctioning of the outer hair cells, language may be affected.

¿El procesamiento coclear está involucrado en los problemas de lenguaje? / Is cochlear processing involved in language disorders?

Introducción. Las emisiones otoacústicas evidencian la existencia de un proceso activo en la cóclea y la motilidad de las células ciliadas externas implica que éstas pueden cambiar la respuesta mecánica coclear. Creemos que un procesamiento inapropiado de los sonidos del lenguaje en la cóclea puede dar como resultado una alteración de los procesos del lenguaje. Sujetos y métodos. Se realizó historia clínica, exploración neurológica, visual y auditiva, escala de inteligencia de Wechsler, prueba de lenguaje inicial (PLI), potenciales evocados auditivos de tallo cerebral (PEATC) y emisiones otoacústicas transitorias. Con los resultados de la PLI se formaron tres grupos: controles, patológicos y patológicos con PLI normal. Resultados. Todos los niños presentaron respuesta a 20 dB por medio de los PEATC. En las emisiones otoacústicas transitorias se realizó la t de Student entre el oído derecho y el izquierdo para la reproducibilidad total y la reproducibilidad por banda de frecuencia dentro de cada grupo, sin observarse diferencias significativas Se efectuó la misma prueba entre los grupos (controles frente a patológicos, controles frente a patológicos con PLI normal y patológicos frente a patológicos con PLI normal) en el oído derecho e izquierdo, sin encontrarse diferencias significativas en la reproducibilidad total para ambos oídos. No se hallaron diferencias significativas en la reproducibilidad por bandas de frecuencia para el oído izquierdo, pero sí para el oído derecho. Conclusión. Existe una lateralidad desde la periferia para el procesamiento del lenguaje y si este proceso no es adecuado, por fallos en la función de las células ciliadas externas, el lenguaje puede verse afectado (AU)

Introduction. Otoacoustic emissions are evidence of the existence of an active process in the cochlea, and the motility of the outer hair cells means that they can change the cochlear mechanical response. We believe that incorrect processing of the sounds of language in the cochlea can result in impaired language processes. Subjects and methods. Data were collected from the patient record; neurological, visual and auditory examination; Weschler intelligence scale; initial language test (ILT); brainstem auditory evoked potentials (BAEPs) and transient otoacoustic emissions. The results of the ILT were used to form three groups: controls, pathological and pathological with normal ILT. Results. All the children presented a response at 20 dB by means of the BAEPs. In the transient otoacoustic emissions, Student’s t test was conducted between the right and the left ear for total reproducibility and reproducibility at different band frequencies within each group. No significant differences were observed. The same test was carried out between groups (controls versus pathological, controls versus pathological with normal ILT, and pathological versus pathological with normal ILT) in the right and left ears; no significant differences were found in the total reproducibility for the two ears. No significant differences were found in the reproducibility at different frequency bands for the left ear, but some were found in the case of the right ear. Conclusions. Laterality from the periphery exists for language processing and if this process fails to perform correctly, due to malfunctioning of the outer hair cells, language may be affected (AU)

[Anatomic and topographic models of the cerebral areas that activates during the linguistic functions]. / Modelos anatomotopográficos de las áreas cerebrales que se activan durante la función lingüística.

AIM: A brief revision was performed in order to develop a topographic model of cerebral activation during silent reading, syllable's repetition and emotional prosody, based in recent neuroimaging studies. DEVELOPMENT: It has been reported that the words are analyzed in both occipital hemispheres during silent reading, after they are 'written' in the right temporal cortex while the integration of the semantic and phonologic processes are integrated on different left temporal areas and also in the left frontal lower part. The understanding is achieved in the left-middle temporal cortex. In the other hand, activation during articulatory movements is carried out in the left supratemporal gyrus and the left motor and premotor cortex, the left putamen and part of both hemispheres of the cerebellum. Finally, recognition of the emotional prosody occurs in three stages: obtaining of the acoustic information in some areas of the right temporal lobe, representation of acoustic sequences in the right posterio-superior temporal area, and an evaluation of the emotional prosody in the lower frontal bilateral cortex, with the involvement of the basal ganglia in the emotional expression. CONCLUSIONS: The location and synchrony of the areas that activate during the language processing is lateralized toward the left hemisphere and it involves cortical and subcortical areas, except for the emotional prosody. The understanding of the language processes will open the field for to take advantage of the plastic mechanisms for the speech therapy and rehabilitation.

Modelos anatomotopográficos de las áreas cerebrales que se activan durante la función lingüística / Anatomic and topographic models of the cerebral areas that activates duringthe linguistic functions

Objetivo. Con el fin de elaborar modelos topográficos de activación cerebral asociados a los procesos de lecturasilenciosa, repetición de sílabas y prosodia emocional, se realiza una breve revisión bibliográfica de los avances recientes en estudios de neuroimagen. Desarrollo. Se ha comunicado que durante la lectura silenciosa, las palabras se analizan en amboshemisferios occipitales, después la palabra se ‘redacta’ en la corteza temporal derecha, mientras que la integración del proceso semántico y el fonológico se realiza en distintas áreas temporales izquierdas y en la parte inferior frontal izquierda. La comprensión se logra en la corteza temporal media izquierda. Por otro lado, la activación durante los movimientos articulatorios se lleva a cabo en el giro supratemporal izquierdo y las cortezas motora y premotora izquierdas, el putamen izquierdo y parte del cerebelo en forma bilateral. Finalmente, el reconocimiento de la prosodia emocional sucede en tres etapas: obtención de la información acústica en áreas del lóbulo temporal derecho, representación de secuencias acústicas en el surco temporal posterosuperior derecho y evaluación de la prosodia emocional en la corteza bilateral frontal inferior, junto con la participación de los ganglios basales en lo que respecta a la expresión emocional. Conclusiones. La localización y sincronizaciónde las áreas que se activan durante los procesos del lenguaje, con excepción de la prosodia emocional, está lateralizada preferentemente hacia el hemisferio izquierdo e implica áreas corticales y subcorticales. El entendimiento de los procesos del lenguaje abrirá el campo para el aprovechamiento de los mecanismos plásticos en la rehabilitación logopédica

Aim. A brief revision was performed in order to develop a topographic model of cerebral activation during silentreading, syllable’s repetition and emotional prosody, based in recent neuroimaging studies. Development. It has been reported that the words are analyzed in both occipital hemispheres during silent reading, after they are ‘written’ in the right temporal cortex while the integration of the semantic and phonologic processes are integrated on different left temporal areas and alsoin the left frontal lower part. The understanding is achieved in the left-middle temporal cortex. In the other hand, activation during articulatory movements is carried out in the left supratemporal gyrus and the left motor and premotor cortex, the left putamen and part of both hemispheres of the cerebellum. Finally, recognition of the emotional prosody occurs in three stages:obtaining of the acoustic information in some areas of the right temporal lobe, representation of acoustic sequences in the right posterio-superior temporal area, and an evaluation of the emotional prosody in the lower frontal bilateral cortex, with the involvement of the basal ganglia in the emotional expression. Conclusions. The location and synchrony of the areas thatactivate during the language processing is lateralized toward the left hemisphere and it involves cortical and subcortical areas, except for the emotional prosody. The understanding of the language processes will open the field for to take advantage of the plastic mechanisms for the speech therapy and rehabilitation

[Evaluation of the motor behavior in rats with cortical ablation]. / Caracterizacion de la conducta motora en ratas con ablacion cortical.

INTRODUCTION: The cortical ablation has been used as an experimental model in order to study the basic mechanisms of functional recovery. However, there is not data concerning to the injury effects on the motor and somatosensorial behavioral manifestations that allow us to categorize such sequels as a hemiplegic model. MATERIALS AND METHODS: We used 35 male Wistar rats (280-300 g) allocated in two groups: control (n = 17) and brain injured by cortical ablation (n = 18). Previously trained, basal recordings of the footprint and motor and somatosensorial assessment were performed in the rats before surgery. The behavioral tests were performed again 6 hours after surgery and the spontaneous ambulatory activity was also evaluated. RESULTS AND CONCLUSIONS: It was observed a decrease in the stride's length and an increase in the stride's angle and in the motor deficit, while the somatosensorial assessment and spontaneous ambulatory activity were not affected. These findings are discussed in function of the motor features of the hemiparetic sequels in humans.

Caracterización de la conducta motora en ratas con ablación cortical / Evaluation of the motor behavior in rats with cortical ablation

Introducción. El modelo de ablación cortical en ratas se ha utilizado para estudiar los mecanismos básicos de recuperación funcional, pero no hay datos respecto a los efectos de la lesión sobre las manifestaciones conductuales motoras y somatosensoriales que permitan categorizar estas secuelas como un modelo de hemiplejía. Materiales y métodos. Se utilizaron 35 ratas machos Wistar (280-300 g), distribuidas en dos grupos: control (n = 17) y con lesión cerebral por ablación cortical(n = 18). Previo entrenamiento, se tomaron registros de la impresión de la huella y de las evaluaciones motora y somatosensorial antes de la cirugía de lesión. Seis horas después de la lesión se realizaron nuevamente las pruebas conductuales y se registró la actividad ambulatoria espontánea. Resultados y conclusiones. Se encontró que la lesión disminuye la longitud e incrementa el ángulo de la zancada y el déficit motor, sin afectar los aspectos somatosensoriales ni la actividad ambulatoriaespontánea. Estos hallazgos se discuten en función de las características motoras de las secuelas hemiparéticas comunicadas en humanos

Introduction. The cortical ablation has been used as an experimental model in order to study the basic mechanismsof functional recovery. However, there is not data concerning to the injury effects on the motor and somatosensorial behavioral manifestations that allow us to categorize such sequels as a hemiplegic model. Materials and methods. We used 35 male Wistarrats (280-300 g) allocated in two groups: control (n = 17) and brain injured by cortical ablation (n = 18). Previously trained, basal recordings of the footprint and motor and somatosensorial assessment were performed in the rats before surgery. The behavioral tests were performed again 6 hours after surgery and the spontaneous ambulatory activity was also evaluated.Results and conclusions. It was observed a decrease in the stride’s length and an increase in the stride’s angle and in the motor deficit, while the somatosensorial assessment and spontaneous ambulatory activity were not affected. These findings arediscussed in function of the motor features of the hemiparetic sequels in humans

Effect of pentobarbital on pH and electrolyte levels after induced seizure in rats.

We studied the effects of high doses of pentobarbital (PB) and carbamazepine (CBZ) on electrolyte levels and pH in an epileptic animal model. Pentobarbital decreased Ca2+ and Na+ levels without pentylenetetrazole (PTZ). After this, Ca2+ and Na+ levels continued to decrease except when CBZ was used, which preserved the Ca2+ levels PTZ may have opposed effects on PB. Our results suggest that PB causes changes in electrolyte levels and pH, but these changes are diminished by CBZ.

Serotonin and 5-hydroxy-indole-acetic acid contents in dorsal raphe and suprachiasmatic nuclei in normal, malnourished and rehabilitated rats under 24 h of sleep deprivation.

It has been discussed that serotonin (5-HT) could be involved in the effects of sleep deprivation (SD) and/or malnutrition (M) on the sleep-wake cycle. The aim of this work was to study the effects of the M, SD and its interaction on 5-HT and 5-hydroxy-indole-acetic acid (5-HIAA) contents in the dorsal raphe (DR) and the suprachiasmatic nuclei (SCN), two sleep-wake cycle regulators. Forty-eight puppets rats were obtained from mothers fed with low or normal casein diet. They were allocated in 3 groups (n=16 each): prenatal/postnatal casein malnutrition (6/6%), prenatal casein malnutrition/nutritional casein rehabilitation (6/25%) and prenatal/postnatal casein well-nourished state (25/25%). When rats were 60 days old, 24 animals were exposed to sleep deprivation by means of forced locomotion during 24 h. The remaining 24 were kept under normal conditions of sleep-wake cycle. Then, all animals were sacrificed by decapitation. DR and SCN were dissected and processed to determine the 5-HT and 5-HIAA contents by means of HPLC. It was observed that 6/6% rats showed a 5-HT increase (DR p<0.011; SCN p<0.019) as well as in SD (DR p<0.0008; SCN p<0.0009) with respect to 25/25% rats. No differences were found in 6/25% rats. Therefore, 5-HIAA decreased significantly in both nuclei in all the groups, notably in M+SD animals (DR p<0.001; SCN p<0.001). We conclude that the sleep-wake cycle disruptions produced by chronic M and SD are mediated in part by a synergistic effect on 5-HT in the DR-SCN pathway, perhaps due to a delay in the development of such brain structures.

Brain monoamine changes in rats after short periods of ozone exposure.

We have shown in our laboratory that cat's and rat's sleep disturbances are produced by 24 h of ozone (O3) exposure, indicating that the central nervous system is affected by this gas. To demonstrate the probable changes in brain neurotransmitters, we evaluated the monoamine contents of the midbrain and striatum of rats exposed to 1 part per million O3 for 1 or 3 hours periods. The results were compared with rats exposed to fresh air and to those exposed to 3 hours of O3 followed by 1 or 3 hours of fresh air. We found a significant increase in dopamine (DA) and its metabolites noradrenaline (NA) and 3,4 dihydroxyphenylacetic acid (DOPAC), as well as an increase in the 5-hydroxyindolacetic acid (5-HIAA) contents of the striatum. There were no changes in homovanillic acid (HVA) and serotonin (5-HT) levels during O3 exposure. Additionally, an increase in DA, NA and 5-HIAA in the midbrain during O3 exposure was observed. Turnover analysis revealed that DA increased more than its metabolites in both the midbrain and striatum. However, the metabolite of 5-HT, i.e. 5-HIAA, increased more than its precursor, this reaching statistical significance only in the midbrain. These findings demonstrate that O3 or its reaction products affect the metabolism of major neurotransmitter systems as rapidly as after 1 h of exposition.

Sleep alterations and brain regional changes of serotonin and its metabolite in rats exposed to ozone.

Sleep alterations and brain regional changes of serotonin were studied in rats exposed to 1.5 ppm of ozone (O3). Results showed a significant decrease in the time spent in wakefulness (W) and paradoxical sleep (PS) and a significant increase in the time spent in slow wave sleep (SWS). Neurochemical analysis showed a significant increase in the metabolism of serotonin in medulla oblongata, pons and midbrain, while both serotonin and its metabolite were reduced in hypothalamus. Although other neurotransmitters could be affected by O3 exposure, the sleep disorders observed in the present work may be related to alterations in the metabolism of serotonin produced by the exposure to O3.