Live predator stress in adolescence results in distinct adult behavioral consequences and dorsal diencephalic brain activation patterns.

Exposure to traumatic events during childhood increases the risk of adult psychopathology, including anxiety, depression, alcohol use disorders and their co-morbidity. Early life trauma also results in increased symptom complexity, treatment resistance and poor treatment outcomes. The purpose of this study was to establish a novel rodent model of adolescent stress, based on an ethologically relevant life-threatening event, live predator exposure. Rats were exposed to a live predator for 10 min. at three different time points (postnatal day (PND)31, 46 and 61). Adult depression-, anxiety-like behaviors and ethanol consumption were characterized well past the last acute stress event (two weeks). Behavioral profiles across assessments were developed to characterize individual response to adolescent stress. CNS activation patterns in separate groups of subjects were characterized after the early (PND31) and last predator exposure (PND61). Subjects exposed to live-predator adolescent stress generally exhibited less exploratory behavior, less propensity to venture into open spaces, a decreased preference for sweet solutions and decreased ethanol consumption in a two-bottle preference test. Additional studies demonstrated blunted cortisol response and CNS activation patterns suggestive of habenula, rostromedial tegmental (RMTg), dorsal raphe and central amygdala involvement in mediating the adult consequences of adolescent stress. Thus, adolescent stress in the form of live-predator exposure results in significant adult behavioral and neurobiological disturbances. Childhood trauma, its impact on neurodevelopment and the subsequent development of mood disorders is a pervasive theme in mental illness. Improving animal models and our neurobiological understanding of the symptom domains impacted by trauma could significantly improve treatment strategies.

Neuropsychological and neuropathological observations of a long-studied case of memory impairment.

We report neuropsychological and neuropathological findings for a patient (A.B.), who developed memory impairment after a cardiac arrest at age 39. A.B. was a clinical psychologist who, although unable to return to work, was an active participant in our neuropsychological studies for 24 y. He exhibited a moderately severe and circumscribed impairment in the formation of long-term, declarative memory (anterograde amnesia), together with temporally graded retrograde amnesia covering ∼5 y prior to the cardiac arrest. More remote memory for both facts and autobiographical events was intact. His neuropathology was extensive and involved the medial temporal lobe, the diencephalon, cerebral cortex, basal ganglia, and cerebellum. In the hippocampal formation, there was substantial cell loss in the CA1 and CA3 fields, the hilus of the dentate gyrus (with sparing of granule cells), and the entorhinal cortex. There was also cell loss in the CA2 field, but some remnants remained. The amygdala demonstrated substantial neuronal loss, particularly in its deep nuclei. In the thalamus, there was damage and atrophy of the anterior nuclear complex, the mediodorsal nucleus, and the pulvinar. There was also loss of cells in the medial and lateral mammillary nuclei in the hypothalamus. We suggest that the neuropathology resulted from two separate factors: the initial cardiac arrest (and respiratory distress) and the recurrent seizures that followed, which led to additional damage characteristic of temporal lobe epilepsy.

Mammillothalamic Disconnection Alters Hippocampocortical Oscillatory Activity and Microstructure: Implications for Diencephalic Amnesia.

Diencephalic amnesia can be as debilitating as the more commonly known temporal lobe amnesia, yet the precise contribution of diencephalic structures to memory processes remains elusive. Across four cohorts of male rats, we used discrete lesions of the mammillothalamic tract to model aspects of diencephalic amnesia and assessed the impact of these lesions on multiple measures of activity and plasticity within the hippocampus and retrosplenial cortex. Lesions of the mammillothalamic tract had widespread indirect effects on hippocampocortical oscillatory activity within both theta and gamma bands. Both within-region oscillatory activity and cross-regional synchrony were altered. The network changes were state-dependent, displaying different profiles during locomotion and paradoxical sleep. Consistent with the associations between oscillatory activity and plasticity, complementary analyses using several convergent approaches revealed microstructural changes, which appeared to reflect a suppression of learning-induced plasticity in lesioned animals. Together, these combined findings suggest a mechanism by which damage to the medial diencephalon can impact upon learning and memory processes, highlighting an important role for the mammillary bodies in the coordination of hippocampocortical activity.SIGNIFICANCE STATEMENT Information flow within the Papez circuit is critical to memory. Damage to ascending mammillothalamic projections has consistently been linked to amnesia in humans and spatial memory deficits in animal models. Here we report on the changes in hippocampocortical oscillatory dynamics that result from chronic lesions of the mammillothalamic tract and demonstrate, for the first time, that the mammillary bodies, independently of the supramammillary region, contribute to frequency modulation of hippocampocortical theta oscillations. Consistent with the associations between oscillatory activity and plasticity, the lesions also result in a suppression of learning-induced plasticity. Together, these data support new functional models whereby mammillary bodies are important for coordinating hippocampocortical activity rather than simply being a relay of hippocampal information as previously assumed.

Reversible Holmes' tremor due to spontaneous intracranial hypotension.

Holmes' tremor is a low-frequency hand tremor and has varying amplitude at different phases of motion. It is usually unilateral and does not respond satisfactorily to drugs and thus considered irreversible. Structural lesions in the thalamus and brainstem or cerebellum are usually responsible for Holmes' tremor. We present a 23-year-old woman who presented with unilateral Holmes' tremor. She also had hypersomnolence and headache in the sitting posture. Her brain imaging showed brain sagging and deep brain swelling due to spontaneous intracranial hypotension (SIH). She was managed conservatively and had a total clinical and radiological recovery. The brain sagging with the consequent distortion of the midbrain and diencephalon was responsible for this clinical presentation. SIH may be considered as one of the reversible causes of Holmes' tremor.

[Bromocriptine: could it be the cure for post-surgical akinetic mutism?] / Bromocriptina: podria ser la cura para el mutismo acinetico posquirurgico?

INTRODUCTION: Akinetic mutism is considered as an alteration of the motivational state of the person, which the patient is unable to initiate verbal or motor responses voluntary, even with preserved sensorimotor and surveillance functions. CASE REPORT: A 43 year-old male involved in a cerebellum arteriovenous fistula complicated with hydrocephalus, who responded dramatically to treatment with bromocriptine. CONCLUSION: Typically, akinetic mutism is described as a transient surgeries posterior fossa. However, it can also occur after multiple valvular failure in patients with hydrocephalus.

TITLE: Bromocriptina: podria ser la cura para el mutismo acinetico posquirurgico?Introduccion. El mutismo acinetico se considera una alteracion del estado motivacional de la persona, por el cual el paciente es incapaz de iniciar respuestas verbales o motoras de caracter voluntario, aun teniendo preservadas las funciones sensomotoras y de vigilancia. Caso clinico. Varon de 43 años, intervenido de una fistula arteriovenosa del cerebelo complicada con hidrocefalia, que respondio espectacularmente al tratamiento con bromocriptina. Conclusion. Tipicamente se ha descrito el mutismo acinetico como una complicacion transitoria de las cirugias de la fosa posterior. Sin embargo, tambien puede aparecer tras multiples fallos valvulares en pacientes con hidrocefalia.

The importance of mammillary body efferents for recency memory: towards a better understanding of diencephalic amnesia.

Despite being historically one of the first brain regions linked to memory loss, there remains controversy over the core features of diencephalic amnesia as well as the critical site for amnesia to occur. The mammillary bodies and thalamus appear to be the primary locus of pathology in the cases of diencephalic amnesia, but the picture is complicated by the lack of patients with circumscribed damage. Impaired temporal memory is a consistent neuropsychological finding in Korsakoff syndrome patients, but again, it is unclear whether this deficit is attributable to pathology within the diencephalon or concomitant frontal lobe dysfunction. To address these issues, we used an animal model of diencephalic amnesia and examined the effect of mammillothalamic tract lesions on tests of recency memory. The mammillothalamic tract lesions severely disrupted recency judgements involving multiple items but left intact both recency and familiarity judgements for single items. Subsequently, we used disconnection procedures to assess whether this deficit reflects the indirect involvement of the prefrontal cortex. Crossed-lesion rats, with unilateral lesions of the mammillothalamic tract and medial prefrontal cortex in contralateral hemispheres, were unimpaired on the same recency tests. These results provide the first evidence for the selective importance of mammillary body efferents for recency memory. Moreover, this contribution to recency memory is independent of the prefrontal cortex. More broadly, these findings identify how specific diencephalic structures are vital for key elements of event memory.

Effect of electrolytic lesions of the dorsal diencephalic conduction system on the distribution of Fos-like immunoreactivity induced by rewarding electrical stimulation.

The dorsal diencephalic conduction system (DDC) is an important pathway of the brain reward circuitry, linking together forebrain and midbrain structures. The present work was aimed at describing the effect of a DDC lesion on the distribution of Fos-like immunoreactivity (FLIR) following intracranial self-stimulation (ICSS) of the lateral hypothalamus (LH). Rats were implanted with monopolar electrodes and divided into three groups; the first two groups were trained to self-stimulate at the LH, whereas the third group received no stimulation and served as a control. Among the two groups that were trained for ICSS, one of them received a lesion at the DDC and was tested for ICSS on the subsequent 5days. On the last day of testing, control rats were placed in operant chambers without receiving any stimulation, and the remaining rats were allowed to receive the stimulation for 1h. All rats were then processed for FLIR. As previously shown, a lesion at the DDC resulted in significant attenuations of the rewarding effectiveness of LH stimulation. Results also show a higher FLIR in several reward-related areas following LH stimulation, especially in the hemisphere ipsilateral to the stimulation electrode. Compared to non-lesioned rats, lesioned animals had lower FLIR in certain brain regions, suggesting that those regions that were activated by the rewarding stimulation may be functionally interconnected with the DDC.

[Brain function recovery after prolonged posttraumatic coma].

OBJECTIVE: To explore the characteristics of brain function recovery in patients after prolonged posttraumatic coma and with long-unconscious states. MATERIAL AND METHODS: Eighty-seven patients after prolonged posttraumatic coma were followed-up for two years. An analysis of a clinical/neurological picture after a prolonged episode of coma was based on the dynamics of vital functions, neurological status and patient's reactions to external stimuli. RESULTS AND CONCLUSION: Based on the dynamics of the clinical/neurological picture that shows the recovery of functions of the certain brain areas, three stages of brain function recovery after a prolonged episode of coma were singled out: brain stem areas, diencephalic areas and telencephalic areas. These functional/anatomic areas of brain function recovery after prolonged coma were compared to the present classifications.

[A role of diencephalic monoaminergic dysfunction in chronic neurogenic pain].

Changes in catecholamine pool (epinephrine, norepinephrine, dopamine) and 5-oxyindoles (serotonin, 5-oxyindolacetic acid) in the diencephalic structures were studied in 2, 15, 40 days of neurogenic pain syndrome development in rats with double-sided entrapment of N. ischiadicus. The main manifestations of monoamine diencephalic dysfunction in the period of neurogenic pain chronization were described: the reduction of catecholamine pool, most evident in the thalamus; absolute and relative serotonin increase (especially in the hypothalamus); "minimization" of thalamus monoamine potential and shift of diencephalic balance to the hypothalamic MA-ergic component domination. The possible mechanisms of the imbalance and its role in the deformation of noci-antinociceptive interaction in the neurogenic pain process are discussed.

The progestin etonogestrel enhances the respiratory response to metabolic acidosis in newborn rats. Evidence for a mechanism involving supramedullary structures.

Central congenital hypoventilation syndrome is a neuro-respiratory disease characterized by the dysfunction of the CO2/H(+) chemosensitive neurons of the retrotrapezoid nucleus/parafacial respiratory group. A recovery of CO2/H(+) chemosensitivity has been observed in some central congenital hypoventilation syndrome patients coincidental with contraceptive treatment by a potent progestin, desogestrel (Straus et al., 2010). The mechanisms of this progestin effect remain unknown, although structures of medulla oblongata, midbrain or diencephalon are known to be targets for progesterone. In the present study, on ex vivo preparations of central nervous system of newborn rats, we show that acute exposure to etonogestrel (active metabolite of desogestrel) enhanced the increased respiratory frequency induced by metabolic acidosis via a mechanism involving supramedullary structures located in pontine, mesencephalic or diencephalic regions.

[Diencephalic syndrome].

Diencephalic structures are thalamus, hypothalamus, epithalamus, subthalamus and hypophysis. Diencephalic structures injury lead to several syndromes: diencephalic dysthermia, hypothalamic obesity, pediatric diencephalic syndrome, Cushing's disease, etc. Diencephalic syndrome manifests in 15-33% of patients with TBI. The goal of our study was to describe diencepalic syndrome in patients in neurointensive care unit. 76 patients took part in the study, 43 women and 33 men among them. The age of patients ranged from 19 to 77 years. All patients had consciousness disorders (CD) and dysnatremia. The patients were divided into 6 groups according to the number of somatic organ dysfunctions (SOD). 12 patients had only dysnatremia and CD without SOD (91.7% of them with benign outcome; 7.3% of them with poor outcome (GOS-3)). 11 patients in the second group had CD, dysnatremia and 1 SOD (45.5% of them had benign outcome; 54.5%--poor outcome). In the third group patients had 2 SOD (42% of them had poor outcome (GOS-3) and 33%--lethal outcome (GOS-1)). The worst outcome was in the 6th group, where patients had 5 SOD. All the patients in that group died. So, in patients with neurosurgical pathology in chiasmal area dienchephalic syndrome manifests by combination of CD, dysnatremia and at least 1 SOD. The number of SOD determines the outcome and severity of diencephalic syndrome.

The ADHD-susceptibility gene lphn3.1 modulates dopaminergic neuron formation and locomotor activity during zebrafish development.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, increased impulsivity and emotion dysregulation. Linkage analysis followed by fine-mapping identified variation in the gene coding for Latrophilin 3 (LPHN3), a putative adhesion-G protein-coupled receptor, as a risk factor for ADHD. In order to validate the link between LPHN3 and ADHD, and to understand the function of LPHN3 in the etiology of the disease, we examined its ortholog lphn3.1 during zebrafish development. Loss of lphn3.1 function causes a reduction and misplacement of dopamine-positive neurons in the ventral diencephalon and a hyperactive/impulsive motor phenotype. The behavioral phenotype can be rescued by the ADHD treatment drugs methylphenidate and atomoxetine. Together, our results implicate decreased Lphn3 activity in eliciting ADHD-like behavior, and demonstrate its correlated contribution to the development of the brain dopaminergic circuitry.

Facilitation of memory by contextual cues in patients with diencephalic or medial temporal lobe dysfunction.

Item-context binding is crucial for successful episodic memory formation, and binding deficits have been suggested to underlie episodic-memory deficits. Here, our research investigated the facilitation of cued recall and recognition memory by contextual cues in 20 patients with Korsakoff's amnesia, 20 unilateral medial-temporal lobectomy (MTL) patients and 36 healthy controls. In a computerized task participants had to learn 40 nouns that were randomly combined with a photograph of an everyday scene. Korsakoff patients showed a general memory deficit in both the cued recall and the recognition condition. A less severe memory impairment was found in the patients with medial-temporal lobectomy. Contextual cues facilitated cued recall to an equal extent in unilateral temporal lobectomy patients and healthy controls. However, no facilitation was observed in Korsakoff patients, suggesting an impairment in item-context binding during cued recall tasks. In contrast to the presumed exclusive dependency of recognition memory on item information, all groups equally profited from the contextual cues in recognition tasks. Our findings show that unilateral lesions as with MTL result in normal binding of context and item information, while bilateral dysfunction of the hippocampal-diencephalic system results in impaired context and item binding.

Diencephalic and brainstem mechanisms in migraine.

Migraine is a common and complex brain disorder. Although it is clear that head pain is a key manifestation of the disorder for most patients, what drives the activation of neuronal pain pathways in susceptible patients is less obvious. There is growing evidence that migraine pathophysiology may, in part, include dysfunction of subcortical structures. These include diencephalic and brainstem nuclei that can modulate the perception of activation of the trigeminovascular system, which carries sensory information from the cranial vasculature to the brain. Dysfunction of these nuclei, and their connections to other key brain centres, may contribute to the cascade of events that results in other symptoms of migraine - such as light and sound sensitivity - thus providing a comprehensive explanation of the neurobiology of the disorder.

Functional maturity of brain structures in children aged 7-8 with differing levels of speech development.

First graders (aged 7-8) in a public elementary school served as subjects for this study. The structural components of their speech were analyzed to determine speech maturity level; total EEG activity was analyzed to assess the functional maturity of brain structures. Results showed that children with levels of speech below the age norm exhibited abnormal EEG patterns suggesting immaturity of the cerebral cortex and fronto-thalamic regulatory system, as well as impairments in the functioning of the mesodiencephalic structures and nonspecific activation systems. Abnormalities in the functioning of brain regulatory systems and the presence of local abnormalities in EEG activity of deep origin are important factors in determining the severity of functional speech impairments.

How does electroconvulsive therapy work? Theories on its mechanism.

This article reviews 3 current theories of electroconvulsive therapy (ECT). One theory points to generalized seizures as essential for the therapeutic efficacy of ECT. Another theory highlights the normalization of neuroendocrine dysfunction in melancholic depression as a result of ECT. A third theory is based on recent findings of increased hippocampal neurogenesis and synaptogenesis in experimental animals given electroconvulsive seizures. Presently, the endocrine theory has the strongest foundation to explain the working mechanism of ECT.

Memory for reward location is enhanced even though acetylcholine efflux within the amygdala is impaired in rats with damage to the diencephalon produced by thiamine deficiency.

A rodent model of diencephalic amnesia produced by thiamine deficiency (pyrithiamine-induced thiamine deficiency [PTD]) was implemented to assess both changes in behavior and acetylcholine (ACh) efflux in the amygdala across four training sessions of a delayed alternation task. Two versions of the delayed alternation task were used. In one version, when a correct alternation was made a unique reward was paired with each spatial location ([left arm-chocolate milk] or [right arm-rat chow]). This paradigm is called the differential outcomes procedure (DOP). In the second version of the task, correct delayed alternation resulted in the same rewards but randomized across location (Nondifferential Outcomes Procedure [NOP]). The PTD rats were impaired on the first session of delayed alternation testing. However, both control and PTD rats using the DOP performed significantly better on delayed alternation than rats trained with the NOP.This effect was driven primarily by the PTD rats in the DOP condition outperforming all other groups on sessions 2-4. Although ACh efflux in the amygdala increased during delayed alternation testing in all groups, the NOP-trained rats had a greater rise in training-related ACh release in the post-training period. This suggests that increased amygdalar cholinergic activation is more critical for processing spatial information than episodic reward information. These data correspond with the idea that cholinergic activation of the amygdala promotes processing in other neural systems.

[Pathophysiology of restless legs syndrome]. / Physiopathologie du syndrome des jambes sans repos.

Restless legs syndrome (RLS) could be the consequence of sensorimotor dysfunction. Dopaminergic treatment has been successful in RLS, suggesting dopaminergic abnormalities. The specific pathophysiology of idiopathic RLS is not well known but recent studies have raised the hypothesis of diencephalospinal pathway dysfunction. This pathway includes spinal, subcortical and cortical structures. In idiopathic RLS, an implication of A11 neurons has been evoked, but further studies are needed to confirm this hypothesis. Brain iron is reduced in RLS. This decrease plays a major role in RLS occurrence. Genetic analyses are necessary to better understand the pathophysiological mechanisms of RLS.

Abnormal cortical network activation in human amnesia: A high-resolution evoked potential study.

Little is known about how human amnesia affects the activation of cortical networks during memory processing. In this study, we recorded high-density evoked potentials in 12 healthy control subjects and 11 amnesic patients with various types of brain damage affecting the medial temporal lobes, diencephalic structures, or both. Subjects performed a continuous recognition task composed of meaningful designs. Using whole-scalp spatiotemporal mapping techniques, we found that, during the first 200 ms following picture presentation, map configuration of amnesics and controls were indistinguishable. Beyond this period, processing significantly differed. Between 200 and 350 ms, amnesic patients expressed different topographical maps than controls in response to new and repeated pictures. From 350 to 550 ms, healthy subjects showed modulation of the same maps in response to new and repeated items. In amnesics, by contrast, presentation of repeated items induced different maps, indicating distinct cortical processing of new and old information. The study indicates that cortical mechanisms underlying memory formation and re-activation in amnesia fundamentally differ from normal memory processing.