The rostromedial tegmental nucleus modulates the development of stress-induced helpless behavior.

A growing body of clinical and preclinical research suggests that structural and functional changes in the habenula, a component of the epithalamus, are associated with major depressive disorder. A major excitatory, efferent projection from the habenula targets the rostromedial tegmentum (RMTg), a mesopontine region that provides significant input to the ventral tegmentum and raphe nuclei. While the RMTg contributes to monoaminergic responses to aversive events, its role in stress-based animal models of depression has yet to be determined. In the present study, we test the hypothesis that the RMTg is a component of the circuitry mediating the development of a maladaptive behavior in which rats repeatedly exposed to inescapable footshock, fail to avoid or escape the same stressor when subsequently given the opportunity to do so. Excitotoxic lesions of the RMTg significantly diminished the frequency of these escape failures 24 h after exposure to inescapable footshock. Conversely, electrical stimulation of the Hb during the initial uncontrollable aversive event, a manipulation that enhances excitatory input to the RMTg, increased the number of trials in which subjects failed to escape an aversive stimulus when presented the option 24 h later. These complementary results provide evidence supporting a role for the RMTg in the expression of stress-induced helpless phenotype and are an important step in understanding the contribution made by this region to the development of depression-related maladaptive behaviors.

Parálisis nuclear del III par craneal en el contexto de un traumatismo craneoencefálico / Nuclear paralysis of the oculomotor nerve within the context of traumatic brain injury

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El cerebro y el daño neuropsiquiátrico de la hipertensión arterial / The brain and neuropychiatric damage of the arterial hypertension

Durante años la protección del cerebro como órgano blanco de la hipertensión arterial ha sido limitada a la prevención del ataque vascular encefálico y sus consecuencias. Sin embargo, en las últimas décadas, otras complicaciones no-neurológicas, tales como el compromiso de las funciones cognitivas y las demencias, parecen ganar espacio. Así, la injuria de los vasos cerebrales secundaria a la hipertensión, en combinación con otros factores (genéticos, depósitos de amiloide), incrementan el riesgo de desarrollar deterioro cognitivo y/o demencia incluida la enfermedad de Alzheimer. Esta revisión pretende demostrar los vínculos entre la hipertensión arterial, el compromiso cognitivo y la demencia, los posibles mecanismos fisiopatológicos que lo explican y el impacto positivo que, el adecuado control de la hipertensión arterial tiene sobre las complicaciones neuropsiquiátricas y en especial sobre la prevención de la enfermedad de Alzheimer

Over the years, protection of the brain as a soft organ of arterial hypertension has been limited to prevention of vascular-encephalic attack and its consequences. However, in recent decades, other non-neurological complications, such as impairment of cognitive functions and dementia seem to be gaining ground. Thus, lesion of the cerebral vessels secondary to hypertension, in combination with other factors (genetics, amyloid deposits), increase the risk of developing cognitive deterioration and/or dementia, including Alzheimer’s disease. This review aims to demonstrate the links between arterial hypertension, cognitive impairment and dementia, possible physiopathological mechanisms that explain it and the positive impact that the adequate control of arterial hypertension has on the neuro-psychiatric complications and especially on prevention of Alzheimer’s disease

The role of the laterodorsal tegmental nucleus in methamphetamine conditioned place preference and locomotor activity.

Methamphetamine (METH) indirectly stimulates the laterodorsal tegmental nucleus (LDT) acetylcholine (ACh) neurons to increase ACh within the ventral tegmental area (VTA). LDT ACh inhibition attenuates METH and saline locomotor activity. The aim of these experiments was to determine whether LDT ACh contributes to METH conditioned place preference (CPP). C57BL/6J mice received a bilateral electrolytic or sham lesion of the LDT. After recovery, mice received alternating pairings of METH (0.5 mg/kg) and saline with distinct tactile floor cues over 8 days. During preference tests, mice were given access to both floor types and time spent on each was recorded. Mice were tested again after exposure to both extinction and reconditioning trials. Brains were then processed for choline acetyltransferase immunohistochemistry to label LDT ACh neurons. Lesioned mice had significantly fewer LDT ACh neurons and showed increased saline and METH locomotor activity during the first conditioning trial compared to sham mice. Locomotor activity (saline and METH) was negatively correlated with the number of LDT ACh neurons. Lesioned and sham mice showed similar METH CPP following conditioning, extinction and reconditioning trials. LDT ACh neurons are not necessary for METH reward as indexed by CPP, but may be important for basal and METH-induced locomotor activity.

Management of migrating intracranial bullets: lessons learned from surviving an AK-47 bullet through the lateral brainstem.

OBJECTIVE: Survival after a gunshot wound (GSW) to the head is becoming more common, with an accompanying increase in spontaneous migration of these intracranial bullet fragments. This phenomenon is well described in current literature and is a potentially life-threatening delayed complication of GSW to the head. METHODS: We present the case of a 17-year-old boy who survived a penetrating GSW to the cranium and cerebellum after an accident involving an AK (Automatic Kalashnikov)-47 (7.62 mm). RESULTS: Following initial attempts to remove the bullet and associated hematoma from the cerebellar hemisphere, intraoperative fluoroscopy revealed that the bullet had migrated to lie within the right middle cerebellar peduncle with the development of intraoperative cardiac arrhythmia. The bullet could not be retrieved without risk of damage to the superior and inferior cerebellar arteries. The patient then developed bacterial meningitis, and further imaging revealed the bullet had again migrated under the cerebellar cortex to an accessible location. The infection was treated with aggressive antibiotic therapy and the bullet was removed from the posterior fossa, thus preventing recurrence of infection and further migration. The patient regained full motor, speech, and proprioceptive function within months after injury. CONCLUSION: The potential for spontaneous migration exists with any penetrating brain injury involving a retained foreign body. When a retained intracranial foreign body is unable to be safely extracted during initial debridement, close clinical evaluation is essential and plain-film or computed tomographic imaging should be considered in order to enhance the early detection of delayed-onset life-threatening deterioration, such as meningitis and occlusion of cerebrospinal fluid drainage, because of spontaneous migration.

Recovery of the corticospinal tract after injury by transtentorial herniation: a case report.

Little is known about recovery of the corticospinal tract (CST) after injury by transtentorial herniation (TH). We present with a patient who showed recovery of the CST after injury by TH, using diffusion tensor tractography (DTT) and transcranial magnetic stimulation (TMS). A 69-year-old female underwent craniotomy and drainage of an intracerebral hemorrhage in the left corona radiata and basal ganglia. Brain CT showed left TH and brain MRI revealed a leukomalactic lesion at the left cerebral peduncle. The patient presented with complete paralysis of the right extremities at ICH onset, but slowly recovered some function to the point of being able to move the affected extremities against gravity at about 6 months after onset. Three-week DTT showed disruption of the left CST below the cerebral peduncle; however, this disruption was recovered on 1-year DTT. Three-week TMS showed no motor evoked potential for the affected hemisphere; in contrast, motor evoked potentials that were compatible with regenerated CST were obtained from the affected hand muscle at 6 months. Using DTT and TMS in a patient with ICH, we demonstrated recovery of the CST after injury by TH.

Síntomas psicológicos y conductuales en deterioro cognitivo leve y enfermedad de Alzheimer / Neuropsychiatric symptoms in mild cognitive impairment and Alzheimer's disease

IntroducciónAnalizar la distribución de los síntomas psicológicos y conductuales de la demencia (SPCD) en mayores con enfermedad de Alzheimer (EA) y deterioro cognitivo leve (DCL) y su utilidad en el diagnóstico diferencial de ambas entidades.Material y métodosCiento setenta y nueve mayores de 64 años diagnosticados de DCL (n = 90) o EA (n = 89), estadio de la Global Deterioration Scale 4 o 5. Se determinaron los SPCD con la escala Neuropsychiatric Inventory. Se describe la prevalencia de los síntomas en cada grupo y se determina el riesgo que supone el presentar cada uno de los SPCD para que un paciente sea diagnosticado de EA en lugar de DCL.ResultadosSesenta y siete pacientes con DCL (74,4%) y 82 con EA (92,1%) presentaron algún SPCD (p<0,01) siendo los más prevalentes la depresión y la apatía en ambos grupos. La media de SPCD fue de 2,1 en los DCL y de 3,2 en los EA y fueron más frecuentes en pacientes con mayores lesiones isquémicas de sustancia blanca (LISB) (p<0,05). La presencia de algún SPCD aumentó el riesgo de que los pacientes fueran diagnosticados de EA en lugar de DCL (odds ratio [OR] de 3,6; intervalo de confianza [IC] del 95%: 1,4–5,7; p<0,01) tras ajustar por edad, sexo, Mini-Mental State Examination y LISB. Los SPCD asociados independientemente al diagnóstico de EA fueron los delirios (OR de 4,9; IC del 95%: 1,3–18,6; p<0,05), la apatía (OR de 2,5; IC del 95%: 1,3–4,7; p<0,01), la desinhibición (OR de 3,1; IC del 95%: 1,5–6,4; p<0,01) y las conductas motoras sin finalidad (OR de 6,3; IC del 95%: 1,7–23,4; p<0,01).ConclusionesLos SPCD son frecuentes en mayores con DCL y EA leve-moderada y pueden ayudar a diferenciar entre estas dos patologías(AU)

Material and methodsA total of 179 subjects, aged more than 64 years old, with either MCI (n=90) or AD (n=89) and Global Deterioration Scale stage 4-5 were studied. NPS were assessed using the Neuropsychiatric Inventory scale. We identified the prevalence of the symptoms in each group and determined the risk conferred by each symptom to the differential diagnosis between the two entities.ResultsSixty-seven patients with MCI (74.4%) and 82 with AD (92.1%) showed at least one NPS (p<0.01), the most prevalent being depression and apathy in both groups. The mean number of NPS was 2.1 in MCI and 3.2 in AD. NPS were more frequent in patients with more white matter ischemic lesions (WMIL) (p<0.05). The presence of at least one NPS increased the risk of being diagnosed with AD rather than MCI (odds ratio [OR] 3.6: 95% confidence interval [CI] 1.4–5.7; p<0.01) adjusted by age, sex, Mini-Mental State Examination and WMIL. The NPS independently associated with a diagnosis of AD were delusions (OR 4.9; 95% CI 1.3–18.6; p<0.05), apathy (OR 2.5; 95% CI 1.3–4.7 p<0.01), disinhibition (OR 3.1; 95% CI 1.5–6.4; p<0.01) and aberrant motor behavior (OR 6.3; 95% CI 1.7–23.4; p<0.01).ConclusionsNPS are frequent in elderly individuals with MCI and mild-moderate AD and may help to differentiate between these two entities(AU9

Dystonia associated with pontomesencephalic lesions.

Secondary dystonia is well known subsequent to lesions of the basal ganglia or the thalamus. There is evidence that brainstem lesions may also be associated with dystonia, but little is known about pathoanatomical correlations. Here, we report on a series of four patients with acquired dystonia following brainstem lesions. There were no basal ganglia or thalamic lesions. Three patients suffered tegmental pontomesencephalic hemorrhage and one patient diffuse axonal injury secondary to severe craniocerebral trauma. Dystonia developed with a delay of 1 to 14 months, at a mean delay of 6 months. The patients' mean age at onset was 33 years (range 4-56 years). All patients presented with hemidystonia combined with cervical dystonia, and two patients had craniofacial dystonia in addition. Three patients had postural or kinetic tremors. Dystonia was persistent in three patients, and improved gradually in one. There was little response to medical treatment. One patient with hemidystonia combined with cervical dystonia improved after thalamotomy. Overall, the phenomenology of secondary dystonia due to pontomesencephalic lesions is similar to that caused by basal ganglia or thalamic lesions. Structures involved include the pontomesencephalic tegmentum and the superior cerebellar peduncles. Such lesions are often associated with fatal outcome. While delayed occurrence of severe brainstem dystonia appears to be rare, it is possible that mild manifestations of dystonia might be ignored or not be emphasized in the presence of other disabling deficits.

Minocycline treatment following hypoxic/ischaemic injury attenuates white matter injury in a rodent model of periventricular leucomalacia.

AIMS: Periventricular white matter injury in premature infants occurs following hypoxia/ischaemia and systemic infection, and results in hypomyelination, as well as neuromotor and cognitive deficits later in life. Inflammatory infiltrates are seen within human cerebral white matter from periventricular leucomalacia (PVL) cases. METHODS: In this study, we examine the time course of CD-68+ microglial cell responses relative to cell death within white matter following hypoxia/ischaemia in a rat model of PVL. We also tested the efficacy of the minocycline, an agent that suppresses microglial activation, in this model when administered as a post-insult treatment. RESULTS: We show that preoligodendrocyte injury in the post-natal day 6 begins within 24 h and continues for 48-96 h after hypoxia/ischaemia, and that microglial responses occur primarily over the first 96 h following hypoxia/ischaemia. Minocycline treatment over this 96 h time window following the insult resulted in significant protection against white matter injury, and this effect was concomitant with a reduction in CD-68+ microglial cell numbers. CONCLUSIONS: These results suggest that anti-inflammatory treatments may represent a useful strategy in the treatment of PVL, where clinical conditions would favour a post-insult treatment strategy.

Kernohan's notch phenomenon in chronic subdural hematoma: MRI findings.

We report two cases of Kernohan's notch phenomenon secondary to chronic subdural hematoma detected by MRI. In the first case, the patient was drowsy with an oculomotor palsy and a hemiparesis ipsilateral to the chronic subdural hematoma. MRI in the post-operative period showed no abnormal signal or deformity of the crus cerebri. The neurological signs immediately resolved after trephination. In the second case, the patient was admitted with progressive decrease in their level of consciousness and ipsilateral hemiparesis with the chronic subdural hematoma. MRI on admission revealed an abnormal signal in the contralateral crus cerebri against the chronic subdural hematoma. After surgery, the mental state gradually recovered to normal with some degree of residual hemiparesis. In patients with chronic subdural hematoma, a compressive deformity of the crus cerebri, without abnormal signal on MRI, may predict a better neurological recovery in patients with Kernohan's notch phenomenon.

Central tegmental field and sexual behavior in the male rat: effects of neurotoxic lesions.

The medial preoptic area/anterior hypothalamus (MPOA/AH) is a key structure in the control of male sexual behavior. This area has reciprocal connections with mesencephalic and brainstem structures including the central tegmental field (CTF). It has been suggested that the CTF receives somatosensory information generated in the genitals promoting activation of the MPOA/AH. In the present study we evaluated the effects of bilateral neurotoxic lesions of the CTF upon male rat sexual behavior. We also explored the effects of these lesions on sociosexual behaviors, partner preference, sexual incentive motivation and motor execution. Tests were performed before and after bilateral quinolinic acid infusions. The lesion was evaluated by quantifying neuronal nuclei (Neu-N) and by the presence of glial fibrillary acidic protein (GFAP) immunohistochemistries. A significant reduction in the percentage of animals displaying mounts, intromissions, and ejaculations was observed in the bilateral and misplaced lesion groups 1 week after the lesion. In the second week post-lesion, only animals with bilateral damage of the CTF showed a significant reduction in sexual behavior. In the third post-lesion test, the percentage of animals displaying sexual behavior returned to control levels. The frequency of pursuit and self-grooming was reduced, and genital exploration was increased after the lesion. Partner preference and sexual incentive motivation were not affected by the lesion suggesting that the CTF is not involved in the appetitive aspects of sexual behavior. Mount, intromission, and ejaculation latency were increased in animals with damage of the CTF and in animals with lesions outside this region. Motor execution was also affected in both groups, suggesting that alterations in latencies could be associated with damage not specific to the CTF.

A test of the opponent-process theory of motivation using lesions that selectively block morphine reward.

The opponent-process theory of motivation postulates that motivational stimuli activate a rewarding process that is followed by an opposed aversive process in a homeostatic control mechanism. Thus, an acute injection of morphine in nondependent animals should evoke an acute rewarding response, followed by a later aversive response. Indeed, the tegmental pedunculopontine nucleus (TPP) mediates the rewarding effects of opiates in previously morphine-naive animals, but not other unconditioned effects of opiates, or learning ability. The aversive opponent process for acute morphine reward was revealed using a place-conditioning paradigm. The conditioned place aversion induced by 16-h spontaneous morphine withdrawal from an acute morphine injection in nondependent rats was abolished by TPP lesions performed prior to drug experience. However, TPP-lesioned rats did show conditioned aversions for an environment paired with the acute administration of the opioid antagonist naloxone, which blocks endogenous opioids. The results show that blocking the rewarding effects of morphine with TPP lesions also blocked the opponent aversive effects of acute morphine withdrawal in nondependent animals. Thus, this spontaneous withdrawal aversion (the opponent process) is induced by the acute rewarding effects of morphine and not by other unconditioned effects of morphine, the pharmacological effects of morphine or endogenous opioids being displaced from opiate receptors.

The role of the dorsolateral tegmentum in the control of male sexual behavior: a reevaluation.

The medial preoptic area/anterior hypothalamus (MPOA/AH) plays a key role in the control of male sexual behavior. Independently of the type, MPOA/AH lesions permanently eliminate male sexual behavior in the rat. The MPOA/AH projects among other structures to the dorsolateral tegmentum (DLT). Bilateral electrolytic lesions of the DLT or the unilateral electrolytic destruction of the MPOA/HA combined with a contralateral electrolytic lesion of the DLT eliminate male sexual behavior. In the present experiment, we evaluated if neurotoxic lesions of the DLT produce the same behavioral deficits as those observed after electrolytic lesions. This would allow us to evaluate if neurons of the DLT or the fibers passing through this area are important in the control of male sexual behavior. To this aim, sexually experience male rats were tested for socio-sexual behavior, partner preference and motor execution in order to determine if the possible behavioral changes could be attributed to alterations in sexual motivation or motor execution. One week after the bilateral DLT lesions the animals were evaluated in the same behavioral tests. The lesions were identified by glial fibrillary acidic protein (GFAP) and neuronal nuclear protein (Neu-N) immunohistochemistry. No significant consistent effects upon sexual behavior were observed in any of the groups, including the group with clear bilateral damage of the DLT. A reduction in the percentage of males displaying ejaculation in the first post-lesion test was observed for all groups injected with quinolinic acid. No effects upon partner preference or motor coordination were observed after the lesion in any of the groups. The lack of effect of DLT neurotoxic lesions upon mating suggests that neurons of this structure are not involved in the control of male sexual behavior.

Effects of lesioning of the medial cervical nucleus on the baseline spike activity of neurons in the central and basolateral nuclei of the amygdala.

Studies of the characteristics of baseline spike activity in the central and basolateral nuclei of the amygdala demonstrated significant differences between these nuclei. Lesioning of the medial cervical nucleus, which is one of the sources of ascending serotoninergic projections of the forebrain, led to marked and generally reciprocal changes in the spike activity of the amygdalar nuclei studied. It is suggested that serotoninergic afferentation from the medial cervical nucleus modulates the activity of amygdalar nuclei with different functional assignments.

Lesions of the Edinger-Westphal nucleus alter food and water consumption.

The Edinger-Westphal nucleus (EW) produces several neuropeptides, including urocortin 1 and cocaine-amphetamine-regulated transcript, which regulate feeding, energy balance, and anxiety. Additionally, the EW projects to feeding and anxiety-regulatory brain areas. The authors tested the effect of lesions of the EW on the consumption of food, water and flavored solutions, metabolic indices, and exploratory behavior on the elevated plus maze in male C57BL/6J mice. EW lesion significantly reduced basal and deprivation-induced food and fluid consumption compared with sham and placement controls, but it did not alter behavior on the elevated plus maze. EW lesion had no effect on indices of basal metabolic activity, including plasma glucose level and body temperature. These effects suggest that the peptidergic neurons of the EW regulate food consumption.

Lesions of the Edinger-Westphal nucleus in C57BL/6J mice disrupt ethanol-induced hypothermia and ethanol consumption.

The Edinger-Westphal nucleus (EW) is a brain region that has recently been implicated as an important novel neural target for ethanol. Thus, the EW is the only brain region consistently showing elevated c-Fos expression following both voluntary and involuntary ethanol administration. Ethanol-induced c-Fos expression in the EW has been shown to occur in urocortin I-positive neurons. Moreover, previous reports using several genetic models have demonstrated that differences in the EW urocortin I system are correlated with ethanol-mediated behaviours such as ethanol-induced hypothermia and ethanol consumption. The aim of this study was to confirm these relationships using a more direct strategy. Thus, ethanol responses were measured following electrolytic lesions of the EW in male C57BL/6J mice. Both EW-lesioned and sham-operated animals were tested for several ethanol sensitivity measures and ethanol consumption in a two-bottle choice test. The results show that lesions of the EW significantly disrupted ethanol-induced hypothermia, while having no effect on pupillary dilation, locomotor activity or ethanol-induced sedation. In addition, EW-lesioned animals showed significantly lower ethanol preference and total ethanol dose consumed in the two-bottle choice test. EW-lesioned animals also consumed less sucrose than sham-operated animals, but did not have altered preferences for sucrose or quinine in a two-bottle choice test. These data support previously observed genetic correlations between EW urocortin I expression and both ethanol-induced hypothermia and ethanol consumption. Taken together, the findings suggest that the EW may function as a sensor for ethanol, which can influence ethanol consumption and preference.

Lesions of the dorsal noradrenergic bundle augment the renin response to blood loss but do not alter hypothalamic Fos expression.

The goal of this study was to determine if the dorsal noradrenergic bundle (DNAB) plays an essential role in mediating increased plasma renin activity (PRA) and hypothalamic activation, as indicated by increased Fos expression, in response to a small volume blood loss in unanesthetized animals. Male Sprague-Dawley rats were prepared with bilateral 6-hydroxydopamine or sham lesions of the dorsal noradrenergic bundle. In both groups of animals, blood pressure decreased by only 10-15 mmHg following hemorrhage (10 ml/kg over 15 min). Plasma renin activity increased similarly in both groups after 5 ml/kg blood loss, but showed a significantly greater increase after 10 ml/kg blood loss in animals with 6-hydroxydopamine lesions than in those with sham lesions (increase of 13.8 +/- 2.0 ng/ml/h versus 8.4 +/- 1.2 ng/ml/h; P < 0.025). There were numerous Fos-immunoreactive cell nuclei in the supraoptic nucleus (SON) and parvicellular paraventricular hypothalamic nucleus (PVN) of hemorrhaged animals. The number of Fos-positive neurons did not differ between groups, indicating that the dorsal noradrenergic bundle does not convey the primary drive for supraoptic and paraventricular nucleus activation during blood loss. However, one or more of the forebrain regions innervated by the dorsal noradrenergic bundle may attenuate the sympathetic outflow that initiates renin release in response to hemorrhage.

Experimental parkinsonism in primates.

Early in the 1960s the primate model of Parkinson's disease was first introduced by placing an electrolytic lesion in the midbrain. In the 1980s, a dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was accidentally shown to induce parkinsonism in humans, and subsequently was confirmed to reproduce an almost perfect model of parkinsonism in primates. In the late 1980s chemical manipulations of the basal ganglia were shown to induce parkinson symptoms, especially dyskinesia, and more recently, chemical lesioning of the pedunculopontine tegmental nucleus has also been shown to induce parkinsonism. We still do not have a perfect animal model of parkinsonism, however, these models have offered excellent opportunities to study the basic mechanisms in parkinsonism and the function of the basal ganglia.

Diazepam modifies the effect of pedunculopontine lesions on morphine but not on amphetamine conditioned place preference.

We have previously shown that T-maze learning impairments caused by lesions to the pedunculopontine tegmental nucleus (PPTg) can be reversed by the anxiolytic diazepam. We now report that diazepam also reverses the effect of PPTg lesions on conditioned place preference (CPP) to morphine but not to amphetamine. Rats with bilateral sham or N-methyl-D-aspartate lesions (0.1 or 0.05 M) to the PPTg were trained in a unbiased CPP paradigm with 2 mg/kg morphine or 2 mg/kg D-amphetamine associated with one compartment of the apparatus and vehicle injections in the alternative compartment. After three drug/saline-compartment pairings, the preference of the animals was assessed by allowing them to explore the entire apparatus for 20 min. In contrast to sham-lesioned subjects, the rats with PPTg lesions did not show a preference for the compartment paired with morphine or amphetamine. In two experiments the expression of a morphine CPP was restored by injecting the lesioned animals with 1 mg/kg of diazepam 30 min before the test session. Diazepam pre-treatment did not restore the expression of amphetamine CPP.