Immuno-modulator inter-alpha inhibitor proteins ameliorate complex auditory processing deficits in rats with neonatal hypoxic-ischemic brain injury.

Hypoxic-ischemic (HI) brain injury is recognized as a significant problem in the perinatal period, contributing to life-long language-learning and other cognitive impairments. Central auditory processing deficits are common in infants with hypoxic-ischemic encephalopathy and have been shown to predict language learning deficits in other at risk infant populations. Inter-alpha inhibitor proteins (IAIPs) are a family of structurally related plasma proteins that modulate the systemic inflammatory response to infection and have been shown to attenuate cell death and improve learning outcomes after neonatal brain injury in rats. Here, we show that systemic administration of IAIPs during the early HI injury cascade ameliorates complex auditory discrimination deficits as compared to untreated HI injured subjects, despite reductions in brain weight. These findings have significant clinical implications for improving central auditory processing deficits linked to language learning in neonates with HI related brain injury.

Auditory cortical function during verbal episodic memory encoding in Alzheimer's disease.

OBJECTIVE: Episodic memory encoding of a verbal message depends upon initial registration, which requires sustained auditory attention followed by deep semantic processing of the message. Motivated by previous data demonstrating modulation of auditory cortical activity during sustained attention to auditory stimuli, we investigated the response of the human auditory cortex during encoding of sentences to episodic memory. Subsequently, we investigated this response in patients with mild cognitive impairment (MCI) and probable Alzheimer's disease (pAD). METHODS: Using functional magnetic resonance imaging, 31 healthy participants were studied. The response in 18 MCI and 18 pAD patients was then determined, and compared to 18 matched healthy controls. Subjects heard factual sentences, and subsequent retrieval performance indicated successful registration and episodic encoding. RESULTS: The healthy subjects demonstrated that suppression of auditory cortical responses was related to greater success in encoding heard sentences; and that this was also associated with greater activity in the semantic system. In contrast, there was reduced auditory cortical suppression in patients with MCI, and absence of suppression in pAD. Administration of a central cholinesterase inhibitor (ChI) partially restored the suppression in patients with pAD, and this was associated with an improvement in verbal memory. INTERPRETATION: Verbal episodic memory impairment in AD is associated with altered auditory cortical function, reversible with a ChI. Although these results may indicate the direct influence of pathology in auditory cortex, they are also likely to indicate a partially reversible impairment of feedback from neocortical systems responsible for sustained attention and semantic processing.

Short-term tropisetron treatment and cognitive and P50 auditory gating deficits in schizophrenia.

OBJECTIVE: The α7 nicotinic acetylcholine receptor (nAChR) is associated with cognitive and P50 auditory gating deficits in schizophrenia, and α7 nAChR agonists can potentially reverse these deficits. The authors examined multiple dosages of tropisetron, a partial agonist at the nAChR, for short-term effects on cognition and P50 deficits in schizophrenia. METHOD: In a randomized double-blind design, 40 nonsmoking patients with schizophrenia who had P50 ratios greater than 0.5 and were stabilized on 3-6 mg/day of risperidone were randomly assigned to receive placebo (N=10) or oral tropisetron at 5 mg/day (N=10), 10 mg/day (N=10), or 20 mg/day (N=10). The authors measured P50 inhibitory gating and administered the Chinese-language version of the Repeatable Battery for the Assessment of Neuropsychological Status at baseline and after 10 days of treatment. RESULTS: After 10 days of treatment, all three daily doses of tropisetron significantly improved overall cognitive deficits, with 10 mg showing the greatest improvement for the immediate memory index score and 20 mg for the delayed memory index score on the cognitive battery. The P50 deficits were also improved, and that improvement was significantly correlated with cognitive improvement. Two patients in the 20 mg/day group dropped out because of adverse effects, but the other dosages were well tolerated. CONCLUSIONS: The improvement of cognition with tropisetron appeared to be associated with normalization in P50 deficits. Thus, α7 nAChR agonists appear to be a promising therapeutic approach for the treatment of cognitive deficits that are related to abnormal P50 suppression in schizophrenia.

Charles Bonnet plus syndrome: apropos of a case.

PURPOSE: Charles Bonnet syndrome plus is an exceedingly rare variant of this disorder. The variant has been described in patients with sight impairment and severe hypoacusis, and is usually characterized by complex visual and auditory--musical--hallucinations that the patients recognize as unreal. METHOD: Case report. RESULTS: A 75-year-old woman diagnosed with Usher syndrome presented with visual acuity of light perception in both eyes, which did not improve with the use of a pinhole occluder. She also had coptosis in right ear and severe hypoacusis in left ear, confirmed through audiometry. Audiometric tests were normal once the implant and the hearing aid were connected. The patient was referred to the Neuro-Ophthalmology Unit after recounting experiencing complex visual hallucinations, as well as auditory (musical) ones at night after disconnecting the hearing aid. She described the latter as a nightly occurrence of hearing "cabaret music." Nevertheless, she was aware of reality and of her sensory impairments. The patient was diagnosed at the interdisciplinary Neuro-Ophthalmology Unit, and began pharmacologic treatment with clear improvement. CONCLUSIONS: Knowledge of Charles Bonnet syndrome and in particular of Charles Bonnet syndrome plus--due to its infrequency--on the part of ophthalmologists is fundamental to adequately diagnose and treat this rare disorder.

Topiramate responsive exploding head syndrome.

Exploding head syndrome is a rare phenomenon but can be a significant disruption to quality of life. We describe a 39-year-old female with symptoms of a loud bang and buzz at sleep onset for 3 years. EEG monitoring confirmed these events occurred in transition from stage 1 sleep. This patient reported improvement in intensity of events with topiramate medication. Based on these results, topiramate may be an alternative method to reduce the intensity of events in exploding head syndrome.

The nicotinic receptor of cochlear hair cells: a possible pharmacotherapeutic target?

Mechanosensory hair cells of the organ of Corti transmit information regarding sound to the central nervous system by way of peripheral afferent neurons. In return, the central nervous system provides feedback and modulates the afferent stream of information through efferent neurons. The medial olivocochlear efferent system makes direct synaptic contacts with outer hair cells and inhibits amplification brought about by the active mechanical process inherent to these cells. This feedback system offers the potential to improve the detection of signals in background noise, to selectively attend to particular signals, and to protect the periphery from damage caused by overly loud sounds. Acetylcholine released at the synapse between efferent terminals and outer hair cells activates a peculiar nicotinic cholinergic receptor subtype, the alpha9alpha10 receptor. At present no pharmacotherapeutic approaches have been designed that target this cholinergic receptor to treat pathologies of the auditory system. The potential use of alpha9alpha10 selective drugs in conditions such as noise-induced hearing loss, tinnitus and auditory processing disorders is discussed.

Olanzapine improves deficient sensory inhibition in DBA/2 mice.

Most schizophrenia patients do not inhibit their P50 auditory evoked potential to the second of duplicate auditory stimuli, reflecting a failure to inhibit responses to irrelevant sensory input. Typical antipsychotic drugs do not improve this deficit while some atypical antipsychotics do. A previous study using an animal model, deficient P20-N40 (which corresponds to the human P50) inhibitory processing in DBA/2 mice found that sensory inhibition was improved by clozapine, the prototypical atypical antipsychotic, but not by haloperidol, a typical antipsychotic. The improvement after clozapine was mediated by alpha7 nicotinic receptors. The present study addresses whether another atypical antipsychotic, olanzapine, will also improve sensory inhibition deficits in the mouse model. In vivo electrophysiological recordings of the P20-N40 auditory evoked potential in anesthetized DBA/2 mice, which spontaneously exhibit a schizophrenia-like inhibitory processing deficit, were obtained after olanzapine alone (0.01, 0.033, 0.1, 0.33 mg/kg, IP) and the efficacious dose of olanzapine (0.033 mg/kg, IP) in combination with either the alpha7 nicotinic receptor antagonist alpha-bungarotoxin or the alpha4beta2 nicotinic receptor antagonist di-hydro-beta-erythroidine. All doses of olanzapine produced improved P20-N40 inhibitory processing in DBA/2 mice. The normalization observed after the 0.033 mg/kg dose of olanzapine was due to a selective decrease in response to the second auditory stimulus indicating an increase in inhibitory processing. This improvement was blocked by pre-administration of alpha-bungarotoxin but not di-hydro-beta-erythroidine. Like clozapine, olanzapine acts via alpha7 nicotinic receptors to elicit improved inhibitory processing of auditory stimuli.

Stimulation of the alpha4beta2 nicotinic receptor by 5-I A-85380 improves auditory gating in DBA/2 mice.

Abnormal auditory gating is a symptom of schizophrenia which has been proposed to be mediated through the alpha7 nicotinic acetylcholine receptor (nAChR). It has been shown that the non-selective nicotinic agonist nicotine has an influence on auditory gating in part by acting on the alpha4beta2 nAChR. The goal of this study was to determine the effect of 5-I A-85380, an agonist for the alpha4beta2 nAChR, in an inbred mouse model with a deficiency for auditory gating. Anesthetized DBA/2 mice were administered 5-I A-85380 alone and in combination with the alpha4beta2 nAChR antagonist, dihydro-beta-erythroidine, or the alpha7 nAChR antagonist, alpha-bungarotoxin. A recording electrode in the CA3 region of the hippocampus recorded P20-N40 waveforms in response to two auditory stimuli. The amplitudes of the response to the first and second clicks were used to determine TC ratios, the measure of auditory gating. 5-I A-85380 significantly decreased the TC ratios by selectively increasing the response amplitudes to the first click with no significant influence on the response amplitudes to the second click. The effect was blocked by dihydro-beta-erythroidine whereas alpha-bungarotoxin had no effect on response amplitude to either click. Although the alpha7 nAChR may mediate the hippocampal response of DBA/2 mice to the second click, the alpha4beta2 nAChR appears to modulate the response to the first click. Thus, the present study implicates the involvement of more than one subtype of nAChR in the auditory gating of DBA/2 mice, specifically the alpha4beta2 nAChR, and its role in the response amplitude to the first stimulus.

Central auditory evaluation in multiple sclerosis: case report.

Herein, we report a case of multiple sclerosis in which peripheral and central hearing, were evaluated through early (brainstem), middle and late auditory evoked potentials before and after corticosteroid therapy. Auditory evaluation revealed better performance on all post-treatment tests. In this case, central auditory function tests (behavioral and electrophysiological) identified the location of the impairment (brainstem), which was in agreement with the patient complaint. The speech in noise test and brainstem auditory evoked potentials are definitely appropriate in confirming brainstem lesions.

Central auditory evaluation in multiple sclerosis: case report / Avaliação auditiva central na esclerose múltipla: relato de caso

Herein, we report a case of multiple sclerosis in which peripheral and central hearing, were evaluated through early (brainstem), middle and late auditory evoked potentials before and after corticosteroid therapy. Auditory evaluation revealed better performance on all post-treatment tests. In this case, central auditory function tests (behavioral and electrophysiological) identified the location of the impairment (brainstem), which was in agreement with the patient complaint. The speech in noise test and brainstem auditory evoked potentials are definitely appropriate in confirming brainstem lesions.

Relatamos caso de esclerose múltipla em que foi feita avaliação da audição periférica e central utilizando os potenciais evocados auditivos de curta, média e longa latência antes e depois da terapia com corticosteróides. A avaliação auditiva revelou melhor desempenho em todos os testes após o tratamento. Neste caso, os testes que avaliam a função central da audição (comportamental e eletrofisiológico) foram capazes de identificar o local da lesão (tronco encefálico), o que estava de acordo com as queixas do paciente. Os testes de fala com ruído e os potenciais evocados auditivos de curta latência são apropriados para revelar lesões de tronco encefálico.

[Clinical characteristics and long-term prognosis of Landau-Kleffner syndrome].

OBJECTIVE: To investigate the clinical and electroencephalographic (EEG) characteristics, therapeutic response and long-term prognosis of Landau Kleffner syndrome (LKS). METHODS: The clinical and EEG data of 10 children with LKS were analyzed, and therapeutic response and long-term outcome were followed up. RESULTS: The age of onset was from 2 to 10.5 years of age. All patients had acquired aphasia, characterized by verbal auditory agnosia. All patients had epileptic seizures. Partial motor seizures during sleep occurred in 8 patients, and other seizure type including atypical absence seizure and generalized tonic-clonic seizure were also observed. Psychological and behavioral abnormalities occurred in 9 patients. There were no abnormalities of hearing and neuro-imaging tests in all patients, and family histories were negative. All the patients had EEG abnormalities. Focal spike and waves of temporal lobe were recorded in 9 patients. Electrical status epilepticus during sleep (ESES) was observed on Video-EEG (VEEG) monitoring in 4 patients. Anti-epileptic drugs (AEDs) showed favorable effects on epileptic seizures, but no effects on aphasia. All patients responded to corticosteroid, and got language improved. Eight patients were followed up for long-term outcome. All patients were seizure free, while the level of language development was abnormal in 5 patients. The VEEG follow-up was conducted in 6 patients. Continuous epileptic discharges in slow sleep recurred in 2 patients after the discontinuation of steroid therapy. CONCLUSIONS: LKS is one of the childhood epileptic encephalopathy, and acquired aphasia and epileptic seizures are two main clinical characteristics. Aphasia is characterized by verbal auditory agnosia. Psychological and behavioral abnormalities are very common in children with LKS. Focal epileptic discharges were often located in temporal area, and usually generalized, and could be continuous during sleep. AEDs could control seizure but had no effects on aphasia. Early use of full dose corticosteroids could improve the language significantly. Long-term follow up showed that language impairments often remained, but the outcome in terms of EEG and epileptic seizure was good.

The effects of antioxidants in the senescent auditory cortex.

We investigated whether a 2-month dietary supplementation of antioxidants, in the form of blueberry phytochemicals, could reverse or retard the age-related decline in temporal processing speed observed in the aged rat. To this end, extracellular single unit responses to frequency modulated (FM) sweeps were recorded in the primary auditory cortex (AI) of aged rats that had been placed on either a blueberry-supplemented or control diet 2 months prior to the physiological recordings. Results showed that most cells recorded from the blueberry-fed rats responded most vigorously to fast FM sweeps, similar to that observed in young rats. In contrast, the majority of cells recorded from the control rats showed a preference for slow FM sweep rates. These results suggest that age-related changes in temporal processing speed in A1 may be reversed by dietary supplementation of blueberry phytochemicals.

Tropisetron improves deficient inhibitory auditory processing in DBA/2 mice: role of alpha 7 nicotinic acetylcholine receptors.

RATIONALE: Deficient inhibitory processing of the P50 auditory evoked potential is a pathophysiological feature of schizophrenia. Several lines of evidence suggest that alpha 7 nicotinic receptors play a critical role in this phenomenon. Similar to schizophrenic patients, DBA/2 mice spontaneously exhibit a deficit in inhibitory processing of the P20-N40 auditory evoked potential, which is thought to be a rodent analog of the human P50 auditory evoked potential. OBJECTIVE: The present study was undertaken to examine whether tropisetron, a partial agonist at alpha 7 nicotinic receptors and an antagonist at 5-hydroxytryptamine-3 receptors, improves this deficit in DBA/2 mice. RESULTS: Administration of tropisetron (1 mg/kg i.p.) significantly improved the deficient inhibitory processing of the P20-N40 auditory evoked potential in DBA/2 mice. Coadministration of methyllycaconitine (MLA; 3 mg/kg i.p.), a partially selective antagonist at alpha 7 nicotinic receptors, significantly blocked the normalizing effect of tropisetron. Furthermore, MLA alone did not alter the deficient inhibitory processing of the P20-N40 auditory evoked potential in DBA/2 mice. CONCLUSIONS: The data suggest that tropisetron improves the deficient inhibitory processing of the P20-N40 auditory evoked potential in DBA/2 mice by effects on alpha 7 and perhaps alpha 4 beta 2 nicotinic receptors. Tropisetron may be useful for the treatment of deficient inhibitory processing in schizophrenia.

Effects of growth hormone on cognitive function.

Whether growth hormone deficiency (GHD) and/or treatment in childhood and adolescence influences cognitive outcome in children with GHD or girls with Turner syndrome (TS) is controversial. Previous studies also suggest that quality of life (QoL) is reduced in adults with GHD, particularly in the areas of social isolation and fatigue. Baseline QoL scores were significantly lower in patients with GHD than in the general population of the same age, gender, and nationality. Unfortunately, few data are available describing QoL in children with GHD. TS is a genetic disorder characterized by short stature, gonadal dysgenesis, and a particular neurocognitive profile of normally developed language abilities (particularly verbal intelligence quotients) and impaired visual-spatial and/or visual-perceptual abilities. This study evaluated the effects of GH treatment on neurocognitive function in girls with TS who were enrolled in a long-term, double-blind, placebo-controlled trial of the effects of GH treatment on final adult height. Treatment duration ranged from 1 to 7 years. The major result of this study was the absence of GH treatment effects on cognitive function in girls with TS. GHD and/or treatment in childhood and adulthood influences cognitive and/or QoL outcomes in some but not all studies. This study did not support a role for GH in influencing the characteristic nonverbal neurocognitive deficits associated with TS. However, evaluation of QoL should be a part of the routine clinical management of patients with GHD or TS.

Boosting GABA improves impaired auditory temporal resolution in the gerbil.

Elderly humans often not only experience peripheral hearing loss but also suffer from more central deficits in temporal auditory processing affecting speech perception. Impaired auditory temporal resolution has also been observed in old rodents. Other studies have demonstrated a reduction of GABAergic function in the auditory pathway of old animals. Here we test the hypothesis that deficits in the GABAergic system affect central auditory processing. Our data suggests that pharmacological augmentation of the GABAergic system ameliorates impaired temporal auditory processing in the gerbil and might be a strategy for the treatment of at least some forms of central hearing loss in humans.

Lithium alters measures of auditory gating in two strains of mice.

BACKGROUND: There are similarities between schizophrenia and bipolar disorder, especially during the psychotic phase. Auditory gating deficits are common in both schizophrenia (does not remit postpsychotic event) and bipolar disorder (only during the manic phase). Lithium has been used to treat psychosis acutely in both bipolar disorder and schizophrenia. An animal model was used to assess the effects of lithium treatment on normal and deficient auditory gating. METHODS: Mice of the DBA/2 (deficient gating) and C3H (normal gating) strains were treated for 6 weeks with either standard rodent chow or rodent chow supplemented with 2.55g/kg lithium carbonate. After 6 weeks of treatment, auditory evoked potentials were recorded under anesthesia. Differences between the groups and treatments were determined using analysis of variance. RESULTS: The normally impaired DBA/2 mice showed improved auditory gating following lithium treatment, while the C3H mice, the benchmark "normal" mouse strain, were impaired after lithium treatment. CONCLUSIONS: C3H mice treated with lithium had significantly impaired auditory gating as a result of treatment. This may be due to norepinephrine facilitation, through a blockade of presynaptic alpha(2) autoreceptors. DBA/2 mice had improved gating as a result of treatment with lithium, likely due to improved functioning of the gamma-aminobutyric acid system.

Clozapine improves deficient inhibitory auditory processing in DBA/2 mice, via a nicotinic cholinergic mechanism.

RATIONALE: Insufficient inhibitory processing of the P50 auditory evoked potential (AEP) is observed in most schizophrenia patients and is not improved by typical antipsychotic drugs, such as haloperidol. This inhibitory processing deficit is associated with a subnormal level of hippocampal alpha7 nicotinic receptors (nAChRs), and drugs that activate these receptors normalize the deficit. The atypical antipsychotic clozapine also normalizes this deficit in schizophrenia patients, but by an unknown mechanism. OBJECTIVE: Similar to schizophrenia patients, DBA/2 mice spontaneously exhibit a deficit in inhibitory processing of the P20-N40 AEP, which is a rodent analogue of the human P50 AEP. The present study determined whether clozapine improved this deficit in DBA/2 mice, and by what mechanism. METHOD: Using a conditioning-testing paradigm with paired auditory stimuli to assess inhibitory P20-N40 AEP processing in DBA/2 mice, the effects of clozapine (0.1, 1, 3.33, or 10 mg/kg, i.p.) and haloperidol (1 mg/kg, i.p.) were assessed. The effect of clozapine (1 mg/kg) was assessed alone and after pre-administration of either alpha-bungarotoxin, an alpha7 nAChR antagonist, or dihydro-beta-erythroidine, an alpha4beta2 nAChR antagonist. RESULTS: In a dose-dependent manner, clozapine improved the deficient inhibitory processing of the P20-N40 AEP normally exhibited by DBA/2 mice. Like alpha7 agonists, 1 mg/kg clozapine selectively increased the inhibition of the P20-N40 response to the second of paired auditory stimuli. The normalizing effect of 1 mg/kg clozapine was blocked by alpha-bungarotoxin, but not by dihydro-beta-erythroidine. Haloperidol did not improve DBA/2's deficient P20-N40 AEP processing. CONCLUSIONS: Clozapine improved the deficient inhibitory processing of the P20-N40 AEP in DBA/2 mice, apparently through stimulation of alpha7 nicotinic receptors. This effect was not shared by the typical antipsychotic haloperidol.

Unilateral musical hallucinations and all that jazz.

A 78-year-old hearing-impaired woman who presented to hospital with a stroke and a subsequent epileptic seizure later developed unilateral musical hallucinations in her better hearing (right) ear. She was found to have a left-sided temporal epileptic focus and the music ceased after a second anti-convulsant was introduced. Comments are made on unusual features of the hallucination and its probable causation.