Neural circuit repair by low-intensity magnetic stimulation requires cellular magnetoreceptors and specific stimulation patterns.

Although electromagnetic brain stimulation is a promising treatment in neurology and psychiatry, clinical outcomes are variable, and underlying mechanisms are ill-defined, which impedes the development of new effective stimulation protocols. Here, we show, in vivo and ex vivo, that repetitive transcranial magnetic stimulation at low-intensity (LI-rTMS) induces axon outgrowth and synaptogenesis to repair a neural circuit. This repair depends on stimulation pattern, with complex biomimetic patterns being particularly effective, and the presence of cryptochrome, a putative magnetoreceptor. Only repair-promoting LI-rTMS patterns up-regulated genes involved in neuronal repair; almost 40% of were cryptochrome targets. Our data open a new framework to understand the mechanisms underlying structural neuroplasticity induced by electromagnetic stimulation. Rather than neuronal activation by induced electric currents, we propose that weak magnetic fields act through cryptochrome to activate cellular signaling cascades. This information opens new routes to optimize electromagnetic stimulation and develop effective treatments for different neurological diseases.

Effects of surgical lesions on choline acetyltransferase activity in the cat cochlea.

Although it is well established that the choline acetyltransferase (ChAT, the enzyme for acetylcholine synthesis) in the mammalian cochlea is associated with its olivocochlear innervation, the distribution of this innervation in the cochlea varies somewhat among mammalian species. The quantitative distribution of ChAT activity in the cochlea has been reported for guinea pigs and rats. The present study reports the distribution of ChAT activity within the organ of Corti among the three turns of the cat cochlea and the effects of removing olivocochlear innervation either by a lateral cut aimed to totally transect the left olivocochlear bundle or a more medial cut additionally damaging the superior olivary complex on the same side. Similarly to results for guinea pig and rat, the distribution of ChAT activity in the cat outer hair cell region showed a decrease from base to apex, but, unlike in the guinea pig and rat, the cat inner hair cell region did not. As in the rat, little ChAT activity was measured in the outer supporting cell region. As previously reported for whole cat cochlea and for rat cochlear regions, transection of the olivocochlear bundle resulted in almost total loss of ChAT activity in the hair cell regions of the cat cochlea. Lesions of the superior olivary complex resulted in loss of ChAT activity in the inner hair cell region of all cochlear turns only on the lesion side but bilateral losses in the outer hair cell region of all turns. The results are consistent with previous evidence that virtually all cholinergic synapses in the mammalian cochlea are associated with its olivocochlear innervation, that the olivocochlear innervation to the inner hair cell region is predominantly ipsilateral, and that the olivocochlear innervation to the outer hair cells is bilateral.

Hypertrophic Olivary Degeneration: A Neurosurgical Point of View.

Hypertrophic olivary degeneration (HOD) is a rare form of transsynaptic degeneration characterized by hypertrophy of the inferior olivary nucleus situated in the olivary body, part of the medulla oblongata, representing a major source of input to the cerebellum. HOD typically results from focal lesions interrupting connections from the inferior olive within the dentato-rubro-olivary pathway, a region also known as the triangle of Guillain-Mollaret (TGM) (red nucleus, inferior olivary nucleus, and contralateral dentate nucleus). Clinically, HOD presents classically as palatal tremor and can include dentatorubral tremor and/or ocular myoclonus. The pathologic changes associated with HOD feature radiologic changes with the inferior olivary nucleus appearing larger and increasing its T2-weighted signal intensity on magnetic resonance images. HOD is commonly managed with pharmacotherapy but may require surgical intervention in extreme cases. HOD has been found to develop as a consequence of any injury that disrupts the TGM pathways (e.g., pontine cavernoma).These findings highlight the critical importance of a thorough knowledge of TGM anatomy to avoid secondary HOD. We present a patient who developed HOD secondary to resection of a tectal plate cavernous malformation and review the literature with an emphasis on the current knowledge of this disorder.

Hypertrophic olivary degeneration resulting from posterior fossa masses and their treatments.

PURPOSE: Characterize hypertrophic olivary degeneration (HOD) that develops from posterior fossa masses and their treatments. METHODS: Retrospectively reviewed MR images and clinical data of 10 patients with posterior fossa masses and HOD. RESULTS: Eight patients had cerebellar lesions, and two patients had pontine lesions. Lesions consisted of tumors, demyelination, and nonspecific necrosis. MRI showed T2 hyperintense signal in the inferior olive a median 86 days after the diagnosis of a posterior fossa lesion. HOD presented prior to surgery (n=2), after surgery (n=3), after surgery/radiation therapy (n=4), or without treatment (n=1). CONCLUSIONS: HOD may develop from posterior fossa masses and surgical and/or radiation therapy.

MR imaging evaluation of inferior olivary nuclei: comparison of postoperative subjects with and without posterior fossa syndrome.

BACKGROUND AND PURPOSE: Posterior fossa syndrome is a severe postoperative complication occurring in up to 29% of children undergoing posterior fossa tumor resection; it is most likely caused by bilateral damage to the proximal efferent cerebellar pathways, whose fibers contribute to the Guillain-Mollaret triangle. When the triangle is disrupted, hypertrophic olivary degeneration develops. We hypothesized that MR imaging patterns of inferior olivary nucleus changes reflect patterns of damage to the proximal efferent cerebellar pathways and show association with clinical findings, in particular the presence or absence of posterior fossa syndrome. MATERIALS AND METHODS: We performed blinded, randomized longitudinal MR imaging analyses of the inferior olivary nuclei of 12 children with and 12 without posterior fossa syndrome after surgery for midline intraventricular tumor in the posterior fossa. The Fisher exact test was performed to investigate the association between posterior fossa syndrome and hypertrophic olivary degeneration on MR imaging. The sensitivity and specificity of MR imaging findings of bilateral hypertrophic olivary degeneration for posterior fossa syndrome were measured. RESULTS: Of the 12 patients with posterior fossa syndrome, 9 had bilateral inferior olivary nucleus abnormalities. The 12 patients without posterior fossa syndrome had either unilateral or no inferior olivary nucleus abnormalities. The association of posterior fossa syndrome and hypertrophic olivary degeneration was statistically significant (P < .0001). CONCLUSIONS: Hypertrophic olivary degeneration may be a surrogate imaging indicator for damage to the contralateral proximal efferent cerebellar pathway. In the appropriate clinical setting, bilateral hypertrophic olivary degeneration may be a sensitive and specific indicator of posterior fossa syndrome.

Inferior olive lesions impair concurrent taste aversion learning in rats.

Taste aversion learning can be established according to two different procedures, concurrent and sequential. For the concurrent task, two different taste stimuli are offered at the same time, one associated with simultaneous intragastric administration of an aversive stimulus and the other associated with physiological saline. This discrimination is learned by sham-lesioned control animals and by animals with lesions in the cerebellar cortex but not by rats lesioned in the inferior olive. At the same time, animals with lesions in the inferior olive and sham-lesioned animals achieve sequential learning when the gustatory stimuli are offered individually during each daily session. The results obtained show that electrolytic lesions in the inferior olive impair acquisition of concurrent learning and are analyzed in terms of an anatomical system consisting of the vagus nerve, inferior olive, and cerebellum, which differentiates between the two modalities of taste aversion learning, concurrent and sequential.

Long-term effects of sectioning the olivocochlear bundle in neonatal cats.

The olivocochlear bundle (OCB) was cut in neonatal cats to evaluate its role in the development of normal cochlear function. Approximately 1 year after deefferentation, acute auditory nerve fiber (ANF) recordings were made from lesioned animals, lesion shams, and normal controls. The degree of deefferentation was quantified via light microscopic evaluation of the density of OCB fascicles in the tunnel of Corti, and selected cases were analyzed via electron microscopy. In the most successful cases, the deefferentation was virtually complete. ANFs from successfully lesioned animals exhibited significant pathophysiology compared with normals and with other animals in which the surgery failed to interrupt the OCB. Thresholds at the characteristic frequency (CF), the frequency at which ANFs are most sensitive, were elevated across the CF range, with maximal effects for CFs in the 10 kHz region. Frequency threshold or tuning curves displayed reduction of tip-to-tail ratios (the difference between CF and low-frequency "tail" thresholds) and decreased sharpness of tuning. These pathological changes are generally associated with outer hair cell (OHC) damage. However, light microscopic histological analysis showed minimal hair cell loss and no significant differences between normal and deefferented groups. Spontaneous discharge rates (SRs) were lower than normal; however, those fibers with the highest SRs remained more sensitive than those with lower SRs. Findings suggest that the interaction between OC efferents and OHCs early in development may be critical for full expression of active mechanical processes.

The olivocerebellar projection mediates ibogaine-induced degeneration of Purkinje cells: a model of indirect, trans-synaptic excitotoxicity.

Ibogaine, an indole alkaloid that causes hallucinations, tremor, and ataxia, produces cerebellar neurotoxicity in rats, manifested by degeneration of Purkinje cells aligned in narrow parasagittal bands that are coextensive with activated glial cells. Harmaline, a closely related alkaloid that excites inferior olivary neurons, causes the same pattern of Purkinje cell degeneration, providing a clue to the mechanism of toxicity. We have proposed that ibogaine, like harmaline, excites neurons in the inferior olive, leading to sustained release of glutamate at climbing fiber synapses on Purkinje cells. The objective of this study was to test the hypothesis that increased climbing fiber activity induced by ibogaine mediates excitotoxic Purkinje cell degeneration. The inferior olive was pharmacologically ablated in rats by a neurotoxic drug regimen using 3-acetylpyridine, and cerebellar damage attributed to subsequent administration of ibogaine was analyzed using immunocytochemical markers for neurons and glial cells. The results show that ibogaine administered after inferior olive ablation produced little or no Purkinje cell degeneration or glial activation. That a lesion of the inferior olive almost completely prevents the neurotoxicity demonstrates that ibogaine is not directly toxic to Purkinje cells, but that the toxicity is indirect and dependent on integrity of the olivocerebellar projection. We postulate that ibogaine-induced activation of inferior olivary neurons leads to release of glutamate simultaneously at hundreds of climbing fiber terminals distributed widely over the surface of each Purkinje cell. The unique circuitry of the olivocerebellar projection provides this system with maximum synaptic security, a feature that confers on Purkinje cells a high degree of vulnerability to excitotoxic injury.

The effects of crossed olivocochlear bundle section on transient evoked otoacoustic emissions.

The purpose of this study was to investigate the effect of sectioning the crossed olivocochlear bundle (COCB) on transient evoked otoacoustic emissions (TEOAEs) in anesthetized adult chinchillas. Of particular interest is the role of cochlear efferents to the outer haircells (OHCs) and how they control mechanisms responsible for otoacoustic emissions. Specifically the experiment addressed whether a tonic level of inhibitory control is reduced by COCB section. The nonlinear component of TEOAEs was measured before and after COCB section. Analysis was made of the 1, 2, 3, 4, and 5 kHz frequency components and of the total emission, as quantified by fast Fourier transform (FFT) of the raw (time domain) response. After COCB section, the amplitude of the total response and of the 2, 3, 4, and 5 kHz components increased whereas the amplitude of the 1 kHz component decreased. The results indicate that COCB section reduces inhibitory control of the OHC mechanisms responsible for nonlinear TEOAE generation. It is not clear whether the nerve section eliminates a spontaneous level of activity in COCB efferents, or whether it results in the interruption of a stimulus-evoked feedback loop.

Reestablishment of the olivocerebellar projection map by compensatory transcommissural reinnervation following unilateral transection of the inferior cerebellar peduncle in the newborn rat.

It is unclear whether reparative processes in the injured mammalian brain are able to restore the topographic organisation of neuronal connections. To address this question, we have investigated the plasticity of the olivocerebellar system. This pathway has a precise topographic arrangement, in which subsets of inferior olivary neurons project to parasagittally oriented Purkinje cell compartments. Following unilateral transection of the inferior cerebellar peduncle in newborn rats, axons from the contralateral projection cross the cerebellar midline and reinnervate the deafferented hemicerebellum. By this experimental approach, we first analysed the behaviour of calcitonin gene-related peptide (CGRP)-immunoreactive climbing fibres. This marker is transiently expressed by a subset of developing inferior olivary axons, which terminate in the cerebellar cortex into several parasagittal strips. We show that transcommissural axons reestablish the original pattern of climbing fibre bands within a few days after lesion. Then, in adult animals injured at birth, we assessed whether the newly formed climbing fibre bands align with zebrin II+/- Purkinje cell compartments, as in normal conditions. The newly formed projection is organised in parasagittally oriented strips which mirror the distribution of their counterparts on the intact side and are precisely aligned to the heterogeneous Purkinje cell compartments. In addition, the patchy distribution of olivo-nuclear fibres suggests that specific reinnervation is also achieved in the deep nuclei. Thus, transcommissural olivocerebellar reinnervation is not random, but it is regulated by selective interactions between distinct subsets of olivocerebellar axons and target neurons aimed at reestablishing the correct projection map.

On the role of the olivocochlear bundle in hearing: 16 case studies.

Earlier we presented data (Scharf et al. (1994) Hear. Res. 75, 11-26) from a young patient (S.B.) who had undergone a vestibular neurotomy, during which the olivocochlear bundle (OCB) was severed. Those data are complemented by measurements on 15 other patients-some like S.B. with normal audiometric thresholds, none with a loss greater than 35 dB at experimental frequencies. Comparisons of performance for the same ear before and after surgery or between the operated and healthy ears do not provide evidence that the lack of OCB input impairs the following psychoacoustical functions: (1) detection of tonal signals, (2) intensity discrimination, (3) frequency selectivity, (4) loudness adaptation, (5) frequency discrimination within a tonal series, (6) in-head lateralization. Data on single-tone frequency discrimination are equivocal. These mostly negative results apply to listening both in the quiet and, where relevant, in noise. The only clear change in hearing after a vestibular neurotomy is that most patients detect signals at unexpected frequencies better than before. This change suggests an impaired ability to focus attention in the frequency domain. Although limited in scope, our finding that human hearing without OCB input is essentially normal agrees with much of the relevant literature on animal behavior and with the patients' self-reports.

Time dependent changes in CRF and its mRNA in the neurons of the inferior olive following surgical transection of the olivocerebellar tract in the rat.

Changes in corticotropin-releasing factor (CRF) immunostaining and CRF mRNA in neurons of the inferior olive were compared following unilateral surgical transections of the olivocerebellar tract. Alterations in CRF immunoreactivity could not be observed earlier than 24 h after surgery. The difference--an accumulation in the contralateral side--was most pronounced at 3 days, and disappeared by the 7th postoperative day. On the other hand, changes in mRNA could be observed as early as 5-30 min after the transection. The most significant accumulation was present at 3 h after the cut and no difference could be observed from the 3rd day following surgery. The results suggest that changes in mRNA levels by axotomy may occur at an earlier time point than previously thought.

Types of neurons and synaptic relations in the lateral superior olive of the cat: normal structure and experimental observations.

Light and electron microscope studies on normal and experimental material in the lateral superior olive (LSO) of cat revealed the presence of three types of neurons: (i) fusiform cells characterized by the large number of terminals articulating with them and projecting to the nuclei of the lateral lemniscus (NLL) and central nucleus of the inferior colliculus (CNIC) (ii) marginal cells embedded in the neuropil of the fibrous capsule and sharing input and output characteristics with the fusiform neurons (iii) multipolar cells with spinous dendrites, local axonal spread and synaptic relation restricted to few afferents only. Four distinct types of axon terminals were distinguished on the basis of their size, vesicle content, membrane attachments, postsynaptic relations and origin. (i) Large terminals with asymmetrical membrane contacts and round vesicles (AR) were of ipsilateral cochlear nucleus origin and articulated predominantly with fusiform and marginal projection cells. (ii) The majority of small AR type terminals arose from the spherical cells of the ipsilateral nucleus of the trapezoid body (NTB). Their number was larger on the fusiform and marginal cells. (iii) Medium sized terminals of symmetrical membrane apposition and pleomorphic vesicles originated from the ipsilateral NLL and CNIC. Their quantitative distribution indicated preference for the multipolar cells. (iv) Profiles with symmetrical membrane contacts and flattened vesicles (SF) type were considered to be terminals of the spinous multipolar interneurons, thus local in origin.

The effect of sectioning auditory centrifugal fibers on the cochlear microphonic and action potential in guinea pigs.

This investigation on 8 guniea pigs determined the immediate effect on the cochlear microphonic (CM) and action potential (AP) of ipsilateral sectoning of the autitory centrifugal fibers. An acoustic signal was used to evoke the CM and AP of one ear of guinea pig and the homolateral olivo-cochlear bundle and lateral lemniscus were then sectioned. Differences between pre- and post-section CM and AP were measured. The results demonstrated an increase in the CM and a decrease in the AP in all animals. Speculation with regard to the overall function of the auditory centrifugal system was offered.