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This chapter reviews the historical perspective of brainstem auditory-evoked potentials (BAEPs) recordings and its intraoperative use. It describes the neurophysiologic basis for the generation of far-field BAEP and methods for monitoring the neural conduction in the auditory pathways using BAEPs and evoked potentials recorded directly from the VIIIth nerve. Monitoring BAEPs is beneficial in operations of large acoustic tumors, posterior fossa procedures, procedures that can compress the brainstem, and other related procedures. BAEPs have improved the outcomes in these complex procedures by giving the surgical team information on the functional status of the auditory pathway from the cochlea through the brainstem.

Object Tinnitus is a prevalent symptom, with clinical, pathophysiological, and treatment features analogous to pain. Noninvasive transcranial magnetic stimulation (TMS) and intracranial auditory cortex stimulation (ACS) via implanted electrodes into the primary or overlying the secondary auditory cortex have been developed to treat severe cases of intractable tinnitus. Methods A series of 43 patients who benefited transiently from 2 separate placebo-controlled TMS sessions underwent implantation of auditory cortex electrodes. Targeting was based on blood oxygen level–dependent activation evoked by tinnitus-matched sound, using functional MR imaging–guided neuronavigation. Results Thirty-seven percent of the patients responded to ACS with tonic stimulation. Of the 63% who were nonresponders, half benefited from burst stimulation. In total, 33% remained unaffected by the ACS. The average tinnitus reduction was 53% for the entire group. Burst stimulation was capable of suppressing tinnitus in more patients and was better than tonic stimulation, especially for noise-like tinnitus. For pure tone tinnitus, there were no differences between the 2 stimulation designs. The average pure tone tinnitus improvement was 71% versus 37% for noise-like tinnitus and 29% for a combination of both pure tone and noise-like tinnitus. Transcranial magnetic stimulation did not predict response to ACS, but in ACS responders, a correlation (r = 0.38) between the amount of TMS and ACS existed. A patient's sex, age, or tinnitus duration did not influence treatment outcome. Conclusions Intracranial ACS might become a valuable treatment option for severe intractable tinnitus. Better understanding of the pathophysiological mechanisms of tinnitus, predictive functional imaging tests, new stimulation designs, and other stimulation targets are needed to improve ACS results.

OBJECTIVE: We report on vascular compression syndrome of the 12th cranial nerve (hypoglossal), an occurrence not previously reported, and demonstrate, through corresponding objective electrophysiological evidence, that microvascular decompression of the hypoglossal nerve root can cure hemilingual spasm. CLINICAL PRESENTATION: A 52-year-old man had lower face muscle twitching and tongue spasms, which worsened with talking, chewing, or emotional stress. Carbamazepine offered only temporary relief, and relief from injections of botulinum toxin was insignificant. He was referred for surgical treatment. High-resolution magnetic resonance imaging of his posterior fossa contents revealed no obvious evidence of any compressive vessel along the facial nerve, but a compressive vessel along the hypoglossal nerve was apparent. INTERVENTION: The presence of preoperative tongue spasms encouraged interoperative monitoring of tongue motor responses. The facial nerve exit zone was explored, but microsurgical inspection of the seventh/eighth cranial nerve complex did not reveal any compressive vessel. However, at the anterolateral aspect of the medulla oblongata, the hypoglossal nerve was clearly compressed and distorted laterally by a large tortuous vertebral artery. When the artery was mobilized away from the nerve, the abnormal late electromyographic response to transcranial electrical stimulation disappeared; immediately after shredded Teflon was interpositioned between the artery and the nerve, the abnormal spontaneous tongue fasciculation also disappeared. The patient has remained spasm free 6 months after surgery. CONCLUSION: Hemilingual spasm may be caused by vascular contact/compression along cranial nerve XII at the lower brainstem and belong to the same family of cranial nerve hyperactivity disorders as hemifacial spasm.

The aim of this paper is to review the effects of activation of neural plasticity and present hypotheses using a systems approach about how activation of neural plasticity can cause symptoms and signs of disease (plasticity diseases).Literature review.It is hypothesized that a program that is initiated by internal or external events controls plastic changes in specific structures of the CNS. Not all structures that have abnormal activity are pathologic but some behave pathological because they receive abnormal input from pathologic structures. The changes in function may remain after the events that elicited the expression of neural plasticity no longer exist.Activation of neural plasticity can have beneficial effects and it can cause symptoms and signs of disease. Activation of neural plasticity can help to adapt to changing demands and it is necessary for normal childhood development of the central nervous system. Plastic changes can cause signs and symptoms of disease by abnormal neural activity in pathologic structures and in structures that receive input from pathologic structures. It is hypothesized that a program controls the plastic changes and that failure in activation of neural plasticity can cause developmental disorders such as autism.

Overstimulation is known to activate neural plasticity in the auditory nervous system causing changes in function and re-organization. It has been shown earlier that overstimulation using high-intensity noise or tones can induce signs of tinnitus. Here we show in studies in rats that overstimulation causes changes in the way place cells of the hippocampus respond as rats search for rewards in a spatial maze. In familiar environments, a subset of hippocampal pyramidal neurons, known as place cells, respond when the animal moves through specific locations but are relatively silent in others. This place-field activity (i.e. location-specific firing) is stable in a fixed environment. The present study shows that activation of neural plasticity through overstimulation by sound can alter the response of these place cells. Rats implanted with chronic drivable dorsal hippocampal tetrodes (four microelectrodes) were assessed for stable single-unit place-field responses that were extracted from multiunit responses using NeuroExplorer computer spike-sorting software. Rats then underwent either 30 min exposure to a 4 kHz tone at 104 dB SPL or a control period in the same sound chamber. The place-field activity was significantly altered after sound exposure showing that plastic changes induced by overstimulation are not limited to the auditory nervous system but extend to other parts of the CNS, in this case to the hippocampus, a brain region often studied in the context of plasticity.

The brain’s ability to change its organization and function is necessary for normal development of the nervous system and it makes it possible to adapt to changing demands but it can also cause disorders when going awry. This property, known as neural plasticity, is only evident when induced, very much like genes. Plastic changes may be programmed and providing a “midcourse correction” during childhood development. If that is not executed in the normal way severe developmental disorders such as autism may results. Normal development of functions and anatomical organization of the brain and the spinal cord depend on appropriate sensory stimulation and motor activations. So-called enriched sensory environments have been shown to be beneficial for cognitive development and enriched acoustic environment may even slow the progression of age-related hearing loss. It is possible that the beneficial effect of physical exercise is achieved through activation of neural plasticity. The beneficial effect of training after trauma to the brain or spinal cord is mainly achieved through shifting functions from damaged brain area to other parts of the central nervous system and adapting these parts to take over the functions that are lost. This is accomplished through activation of neural plasticity. Plastic changes can also be harmful and cause symptoms and signs of disorders such as some forms of chronic pain (central neuropathic pain) and severe tinnitus. We will call such disorders “plasticity disorders”.

Tinnitus is not a single disease but a group of different diseases with different pathologies and therefore different treatments. Regarding tinnitus as a single disease is hampering progress in understanding of the pathophysiology of tinnitus and perhaps, more importantly, it is a serious obstacle in development of effective treatments for tinnitus. Subjective tinnitus is a phantom sound that takes many different forms and has similarities with chronic neuropathic pain. The pathology may be in the cochlea, in the auditory nerve, or, most commonly, in the brain. Like chronic neuropathic pain tinnitus is not life threatening but influences many normal functions such as sleep and the ability to concentrate on work. Some forms of chronic tinnitus have two components, a (phantom) sound and a component that may best be described as suffering or distress. The pathology of these two components may be different and the treatment that is most effective may be different for these two components. The most common form of treatment of tinnitus is pharmacological agents and behavioral treatment combined with sound therapy. Less common treatments are hypnosis and acupuncture. Various forms of neuromodulation are becoming in use in an attempt to reverse maladaptive plastic changes in the brain.

Introduction: Some forms of tinnitus are considered to be auditory phantom phenomena related to reorganization and hyperactivity of the auditory central nervous system. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive tool capable of modulating human brain activity, using single pulse or burst stimuli. Burst rTMS has only been performed in the theta range, and has not been used clinically. The authors analyze whether burst TMS at theta (5 Hz), alpha (10 Hz) and beta (20 Hz) frequencies can temporarily suppress narrow band noise/white noise tinnitus, which has been demonstrated to be intractable to tonic stimulation. Methods: rTMS is performed both in tonic and burst mode in 46 patients contralateral to the tinnitus side, at 5, 10 and 20 Hz. Fourteen placebo negative rTMS responders are further analyzed. Results: In 5 patients, maximal tinnitus suppression is obtained with theta, in 2 with alpha and in 7 with beta burst stimulation. Burst rTMS suppresses narrow band/white tinnitus much better than tonic rTMS t(13)=6.4, p

Hemifacial spasm can be cured by microvascular decompression (MVD) operations of the root exit zone of the facial nerve. This fact was the basis for the (“ephaptic”) hypothesis stating that the anatomical location of the pathology that generates the signs of HFS, spasm in the mimic muscle on one side of the face and synkinesis, was the root exit zone of the facial nerve. However, later intracranial recording from the facial nerve provided strong experimental support of a different hypothesis about the pathology of HFS, namely, that the anatomical location of the pathology is the facial motonucleus.

Disabling positional vertigo (DPV) and some forms of tinnitus can be treated successfully with microvascular decompression (MVD) of the root of the auditory-vestibular nerve. These two diseases have many different forms and the operation is more complex than MVD for trigeminal neuralgia or hemifacial spasm. Success of DPV depends on correct selection of candidates for the treatments. In a study of 41 patients operated upon for severe DPV, 73.2 % were totally free of DPV symptoms or experienced significant improvements that allowed them to return to nearly normal life, 4.9 % had minor relief of symptoms, and 22 % had no noticeable improvement. Other studies have shown that treatment with medications of the benzodiazepine family such as Valium is effective in some individuals who have DPV symptoms.

The only FDA approved treatment for ischemic strokes is tissue plasminogen activator (tPA). The benefit of treatment with tPA is limited and it has to be administrated within a short time window; furthermore, the side effects are serious including increased risk of subsequent hemorrhagic transformation. This review discusses minocycline’s role in neuroprotection, and it discusses the results of five published clinical trials regarding the use of administration of minocycline for treatment of acute stroke. The studies find that the benefit of tPA treatment alone is limited and has serious side effects. While many new agents have been studied to ameliorate this, minocycline, a tetracycline antibiotic, seems the most promising. Some investigators have suggested that administration of minocycline may be suitable as a general treatment of patients with acute stroke that is safe and can be used in both ischemic and hemorrhagic strokes as a single treatment that may provide benefits in reducing the deficits from ischemic stokes with little side effects.

To test the hypothesis that some of the abnormal sensory perceptions that characterize autism may be explained by an abnormal activation of non-classical (extra-lemniscal) sensory pathways.Twenty-one individuals, 18--45 years of age who were diagnosed with autism participated in the study. Sounds (clicks presented at a rate of 40 per second and 65 dB above the normal threshold) were applied through earphones. Electrical stimulation (100 microS rectangular impulses at a rate of 4 per second) was applied through electrodes placed on the skin over the median nerve at the wrist. The participants were asked to match the loudness of the sound with and without the electrical stimulation applied to the median nerve.Electrical stimulation of the median nerve at the wrist in individuals with autism could change the perception of loudness of sounds presented to one ear through an earphone showing a statistically significant abnormal sensory cross-modal interaction.We interpreted our results to support the hypothesis that some individuals with autism have an abnormal cross-modal interaction between the auditory and the somatosensory systems. Cross-modal interaction between senses such as hearing and the somatosensory system does not occur normally in adults. As only the non-classical (extralemniscal) ascending auditory pathways receive somatosensory input, the presence of cross-modal interaction in autistic individuals is a sign that autism is associated with abnormal involvement of the non-classical auditory pathways, implying that sensory information is processed by different populations of neurons than in non-autistic individuals.

✓ Tinnitus is a distressing symptom that affects up to 15% of the population for whom no satisfactory treatment exists. The authors present a novel surgical approach for the treatment of intractable tinnitus, based on cortical stimulation of the auditory cortex.Tinnitus can be considered an auditory phantom phenomenon similar to deafferentation pain, which is observed in the somatosensory system. Tinnitus is accompanied by a change in the tonotopic map of the auditory cortex. Furthermore, there is a highly positive association between the subjective intensity of the tinnitus and the amount of shift in tinnitus frequency in the auditory cortex, that is, the amount of cortical reorganization. This cortical reorganization can be demonstrated by functional magnetic resonance (fMR) imaging.Transcranial magnetic stimulation (TMS) is a noninvasive method of activating or deactivating focal areas of the human brain. Linked to a navigation system that is guided by fMR images of the auditory system, TMS can suppress areas of cortical plasticity. If it is successful in suppressing a patient's tinnitus, this focal and temporary effect can be perpetualized by implanting a cortical electrode.A neuronavigation-based auditory fMR imaging-guided TMS session was performed in a patient who suffered from tinnitus due to a cochlear nerve lesion. Complete suppression of the tinnitus was obtained. At a later time an extradural electrode was implanted with the guidance of auditory fMR imaging navigation. Postoperatively, the patient's tinnitus disappeared and remains absent 10 months later.Focal extradural electrical stimulation of the primary auditory cortex at the area of cortical plasticity is capable of suppressing contralateral tinnitus completely. Transcranial magnetic stimulation may be an ideal method for noninvasive studies of surgical candidates in whom stimulating electrodes might be implanted for tinnitus suppression.

OBJECTIVE The functional anatomy (i.e., tonotopy) of the human cochlear nerve is unknown. A better understanding of the tonotopy of the central nervous system segment of the cochlear nerve and of the pathophysiology of tinnitus might help to ameliorate the disappointing results obtained with microvascular decompressions in patients with tinnitus. METHODS We assume that vascular compression of the cochlear nerve can induce a frequency-specific form of hearing loss and that when the nerve is successfully decompressed, this hearing loss can recuperate. Thirty-one patients underwent a microvascular decompression of the vestibulocochlear nerve for vertigo or tinnitus. Preoperative audiograms were subtracted from postoperative audiograms, regardless of the surgical result with regard to the tinnitus and vertigo, because the hearing improvement could be the only sign of the vascular compression. The frequency of maximal improvement was then correlated to the site of vascular compression. A tonotopy of the cochlear nerve was thus obtained. RESULTS A total of 18 correlations can be made between the site of compression and postoperative maximal hearing improvement frequency when 5-dB hearing improvement is used as threshold, 13 when 10-dB improvement is used as threshold. A clear distribution can be seen, with clustering of low frequencies at the posterior and inferior side of the cochlear nerve, close to the brainstem, and close to the root exit zone of the facial nerve. High frequencies are distributed closer to the internal acoustic meatus and more superiorly along the posterior aspect of the cochlear nerve. CONCLUSION The tonotopic organization of the cisternal segment of the cochlear nerve has an oblique rotatory structure as a result of the rotatory course of the cochlear nerve in the posterior fossa. Knowledge of this tonotopic organization of the auditory nerve in its cisternal course might benefit surgeons who perform microvascular decompression operations for the vestibulocochlear compression syndrome, especially in the treatment of unilateral severe tinnitus.

Auditory information ascends through the brainstem to the cerebral cortices in two parallel pathways, known as the classical and the non-classical ascending auditory pathways. The importance of the non-classical auditory pathway for hearing in humans is unknown but its subcortical connection to limbic structures may be important in tinnitus. In this study we show evidence that non-classical pathways are involved in loudness perception in young individuals but not in adults. We used the fact that some neurons in the non-classical auditory pathways receive somatosensory input and we determined the effect on loudness perception of monaural sounds from electrical stimulation of the median nerve at the wrist. Stimulation of the somatosensory system had the greatest effect on loudness perception in the youngest children that we studied (7-8 years) and the effect was minimal for individuals above 20 years of age. The effect was an increase in loudness in 20 of the 40 individuals we studied and a decrease in 4 individuals; 16 experienced no noticeable change in loudness during somatosensory stimulation.

Plastic changes play an important role in the recovery of motor and sensory functions after ischemic strokes and other forms of injury to the central nervous system. The deficits from ischemia may be exacerbated by immune reactions from the decay products of cells that have died as a result of the ischemia. Recovery from deficits after strokes is mainly achieved through activation of neural plasticity. Recent studies have shown that enhancing activation of neuroplasticity through vagus nerve stimulation (VNS) has a beneficial effect on recovery. It has been also shown that suppression of the immune reaction through administration of minocycline can improve recovery from deficits significantly. The role of the vagus nerve in controlling the immune system suggests that VNS may also be beneficial in reducing injuries to the brain caused by harmful immune reactions.

The pathophysiology of trigeminal neuralgia, hemifacial spasm and other disorders that can be cured by microvascular decompression of cranial nerves, is reviewed and different hypotheses about its pathophysiology are discussed. It is found that the pathophysiology of these disorders is complex and other factors than vascular compression are necessary to cause symptoms. While the efficacy of the microvascular decompression (MVD) operation is indisputable, it is questionable if the symptoms and signs of these disorders are caused by abnormal neural activity in the respective cranial nerves that result from the compression from a blood vessel. Instead, studies point to hyperactivity and hyperexcitability of the respective nuclei as a cause of the symptoms and signs of these disorders. Results of several studies indicate that irritation of the cranial nerve in question from close contact with a blood vessel may promote such development, and it seems necessary that other factors in addition to the vascular contact must be present in order that such a condition develops.

The development of the microvascular decompression (MVD) operation is reviewed. It is stressed that a few innovative neurosurgeons discovered the role of vascular compression of cranial nerves V and VII in trigeminal neuralgia (TGN) and hemifacial spasm (HFS) and developed an operation, later to be known as the MVD operation. While the understanding of the pathophysiology of these disorders has improved, the surgical procedure has undergone little change since Gardner described the operation about 1960.

Intraoperative prolongation of the latency and decrement of the amplitude of peak V of brainstem auditory evoked potentials (BAEP) were studied in 38 microvascular decompression operations in which prolongation of the latency of peak V exceeded 1.0 msec. Postoperative hearing tests of all patients were compared with their preoperative hearing tests. Postoperative hearing loss was unrelated to the maximum prolongation of latency, but the amplitude decreased to lower values in patients with postoperative hearing loss compared to patients whose postoperative hearing was unchanged (P

The development of sudden postoperative hearing loss as a complication of microvascular decompression (MVD) operations in the cerebellopontine angle has already been reported. A sudden hearing loss of vascular origin may also occur hours or days after such operations, but even in such cases an improvement of hearing over the following weeks is possible. Here we report on a gradual deterioration of hearing over a period of two weeks after MVD which has not been described in the literature up to now.A MVD operation was performed twice on a 36 year old patient with trigeminal neuralgia. After the second operation the patient developed a slight hearing impairment 3 days postoperatively which increased over a period of two weeks and ended up with total deafness. The course of intra-operative brainstem auditory evoked potentials and postoperative audiograms is documented.Because of gradual development of the delayed hearing loss, we conclude that postoperative tissue scarring may be the underlying pathology.

The threshold of sensation and the threshold of pain in response to electrical stimulation (impulses of 1 msec duration) of the skin on the forearm or hand in individuals without pain were compared with the thresholds of individuals with chronic pain in the range 1 to 100 pulses per second repetition rate. The threshold of sensation in patients without pain was little affected by the repetition rate of the stimulation within the range studied, and the threshold for pain decreased exponentially with increasing repetition rate. In individuals with chronic pain the threshold of sensation was similar to that of individuals without pain over the entire range of stimulus repetition rates studied, but the threshold ofpain in patients with pain was lower and less affected by the stimulus rate than it was in the individuals without pain, thus closer to the threshold of sensation. [Neural Res 1997; 19: 481-488J

Recent investigations in the authors' laboratory have shown that acute tone exposure (4 kHz continuous tone, 104 dB sound pressure level (SPL), 30-min duration) induces increases in the amplitude of click-evoked potentials in the inferior colliculus (IC). These increases have been attributed to a decrease in GABAA-mediated inhibition on IC neurons. In the present study, we examined the effects of three compounds (diazepam, clonazepam, and (-)-baclofen) that are known to enhance GABAergic inhibition on these tone exposure-induced increases and on changes in temporal integration in the IC. (-)-Baclofen was the only one of the three compounds tested that reversed in a dose-dependent manner the effects of tone exposure on both the amplitude of the click-evoked potentials recorded from the IC and on measures of the changes in temporal integration based on these potentials. Diazepam and clonazepam exhibited remarkably different effects on the click-evoked potentials recorded from the surface of the IC. Diazepam caused a dose-dependent decrease in one of the components of the IC potentials that reflects postsynaptic activity in the IC, whereas clonazepam caused a dose-dependent decrease in a peak that reflects input to the IC from the superior olivary complex (SOC). At dosages up to 40 mg/kg, neither diazepam nor clonazepam reversed the changes in temporal integration in the IC that were induced by the tone exposure; diazepam caused a small, but statistically significant, enhancement of the effects of tone exposure on this function. The results of this study show that (-)-baclofen is a potent modulator of both the excitability of neurons in the ascending auditory pathway and the processing of auditory information by IC neurons. The finding of the present study that two benzodiazepines (clonazepam and diazepam) have remarkably different effects on evoked potentials, which reflects both input to the IC and postsynaptic events in the IC neurons, suggests heterogenicity of the GABAA receptor from one structure to another in the ascending auditory pathway. We suggest that (-)-baclofen may be clinically useful in treating disorders of the auditory system that are caused by plasticity in the ascending auditory pathway.

Recent investigations have implicated that the central nervous system has a role in the changes that occur in auditory function following acoustic trauma caused by noise exposure. These investigations indicate that the inferior colliculus may be the primary anatomical location in the ascending auditory pathway where noise-induced neuronal plasticity occurs, thereby resulting in changes in the neuronal processing of auditory information. In the present investigation, we show that the amplitudes of all peaks in the click-evoked response from the external nucleus of the inferior colliculus decrease during a 30 min exposure to a tone (104 dB sound pressure level (SPL) at 4 kHz and 8 kHz). After tone exposure, the amplitudes of two of the peaks of the response from the external nucleus of the inferior colliculus that reflect the input from more caudal structures slowly returned to baseline levels, whereas the amplitudes of the two peaks reflecting neuronal activity in the inferior colliculus increased above baseline levels and remained at the increased levels for at least 90 min following exposure to the tone. We also show that exposure to a 4 kHz tone at 104 dB SPL causes changes in the neuronal processing of tonebursts in the form of changes in the temporal integration function for one of the peaks of the response from the external nucleus of the inferior colliculus that originates in the inferior colliculus. Before tone exposure the amplitude of this peak decreased with increasing stimulus duration, but after tone exposure the amplitude of this peak was independent of the duration of the toneburst stimulus. We interpret these changes as evidence that noise exposure (tone exposure) causes changes in the excitability of the inferior colliculus that are not seen in more caudal structures, and these changes are probably a result of a change in the balance between inhibition and excitation in the inferior colliculus.

The neural generators of the brainstem auditory evoked potentials (BAEPs) in humans are not completely known. Attempts to identify the anatomical location of the neural generators of the human BAEP based on the results of studies in animals commonly used in auditory experimentation have been difficult because of the considerable anatomical differences between the ascending auditory pathways in humans and animals. The authors of this study compared recordings obtained from different locations on the lateral side of the brainstem in six patients undergoing microvascular decompression surgery for a cranial nerve disorder affecting the fifth cranial nerve (i.e., trigeminal neuralgia). Ipsilateral click stimulation evoked prominent responses from the caudal aspect of the pons up to the junction between the pons and the midbrain, but all components of the responses with latencies shorter than 8 msec had smaller amplitudes when recorded at more rostral locations. Components with latencies in the range of peak V elicited by contralateral click stimulation had their largest amplitudes when recorded from the lateral brainstem at the level of the fourth cranial nerve (thus, close to the inferior colliculus). Earlier components of the contralateral responses (latencies in the range of the latency of peak III) had their largest amplitudes when recorded from the caudal lateral brainstem. The results of this study indicate that the part of the uncrossed auditory pathway that is located rostral to the cochlear nucleus contributes little to the farfield potentials (i.e., BAEP), and it is doubtful whether the contralateral response that can be recorded at the level of the cochlear nucleus contributes noticeably to the BAEP.

The drug baclofen is a potential treatment for severe tinnitus, but its action in relieving tinnitus is not known. Baclofen is available as an approved drug only in racemic form with about equal content of the two enantiomers. In the present paper we show that l-baclofen causes a considerable (40.7%) suppression of the amplitude of the second peak in the click-evoked response from the cochlear nucleus. Bipolar recordings from the external nucleus of the inferior colliculus showed that l-baclofen caused a reduction in the amplitude of three or four distinct peaks in this response. d-Baclofen had no detectable effect on the response from the cochlear nucleus, and had only a slight effect on one component of the response from the external nucleus of the inferior colliculus. The demonstrated effect of l-baclofen on excitation in the ascending auditory pathway indicates that this drug may be a potential treatment for hyperactive auditory disorders such as tinnitus and hyperacusis.

We studied responses from the masseter and nasalis muscles following magnetic stimulation (magStim) and compared these responses with those obtained by direct electrical stimulation of the trigeminal (NV) and facial (NVII) nerve near the root exit zone during microvascular decompression operations of NVII. We found that (1) magStim threshold to excite the nerve is high for NV and low for NVII; (2) excitation of all motor fibers is impossible for NV, and easy for NVII; (3) optimal coil placement is critical for NV, but not critical for NVII; and (4) between and within subjects, the excitation site is variable on NV, but stable on NVII. We estimated that the anatomical location of magStim to be either within or outside the cerebrospinal fluid for NV, and to be in the labyrinthine segment of the facial canal for NVII. Physical models explain and clinical lesion models support these differences found between NV and NVII.

The functional organization of cortical and subcortical networks can be altered by sensory experience. Sensory deprivation destabilizes neural networks resulting in increased excitability, greater neural synchronization and increased spontaneous firing in cortical and subcortical neurons. This pathological activity is thought to generate the phantom percept of chronic tinnitus. While sound masking, pharmacotherapy and cortical stimulation can temporarily suppress tinnitus for some patients, these interventions do not eliminate the pathological activity that is responsible for tinnitus. A treatment that could reverse the underlying pathology would be expected to be effective in alleviating the symptoms, if not curative. Targeted neural plasticity can provide the specificity required to restore normal neural activity in dysfunctional neural circuits that are assumed to underlie many forms of tinnitus. The forebrain cholinergic system and the noradrenergic system play a significant role in modulating cortical plasticity. Stimulation of the vagus nerve is known to activate these neuromodulatory pathways. Our earlier studies have demonstrated that pairing sounds with either nucleus basalis of Meynert (NB) stimulation or vagus nerve stimulation (VNS) generates highly specific and long-lasting plasticity in auditory cortex neurons. Repeatedly pairing tones with brief pulses of VNS reversed the physiological and behavioral correlates of tinnitus in noise exposed rats. We also recently demonstrated that VNS modulates synchrony and excitability in the auditory cortex at least in part by activation of muscarinic acetylcholine receptors, suggesting that acetylcholine is involved in the mechanism of action of VNS. These results suggest that pairing sounds with VNS provides a new avenue of treatment for some forms of tinnitus. This paper discusses neuromodulation as treatment for tinnitus with a focus on the potential value of pairing VNS with sound stimulation as a treatment of chronic tinnitus.

Chronic microvascular compressions of the eighth nerve induce a slowing down of signal transmission in the auditory nerve, electrophysiologically characterized by IPL I-III prolongation. The authors hypothesize this is compensated by an active slowing down of signal transmission of the contralateral input at the level of the brainstem, characterized by contralateral IPL III-V prolongation. Differences between ipsilateral and contralateral IPL I-III and IPL III-V are analyzed before and after microvascular decompression. ABR diagnostic criteria for microvascular compression are ipsilateral IPL I-III prolongation or ipsilateral peak II decrease + ipsilateral IPL I-III prolongation. With IPL I-III as diagnostic criterion, unlike preoperatively the difference between the ipsi- and contralateral IPL I-III is significant postoperatively. When using the stricter diagnostic criterion of IPL I-III + peak II, there is a preoperative significant difference between ipsi- and contralateral IPL I-III, but postoperatively the difference between the ipsi- and contralateral IPL I-III is not significant. Preoperatively, there is a marginal significant difference between the ipsi- and contralateral IPL III-V, which disappears postoperatively.

We recorded evoked potentials from the facial motonucleus of rats in response to electrical stimulation of the temporal branch of the facial nerve in which chronic irritation from a blood vessel had caused the development of an abnormal muscle response. The abnormal muscle response that can be recorded from face muscles that are innervated by one branch of the facial nerve in response to electrical stimulation of a different branch is regarded to be a sign of hemifacial spasm. In the recordings from the motonucleus in rats that showed such an abnormal muscle response (model rats) there was a late component at a latency of about 5 msec, in addition to the early component with a latency of 1.5-2.5 msec that is also observed in normal rats. The latency of the electromyographic potentials recorded from the mentalis-orbicularis oris muscles in response to stimulation of the facial motonucleus was about 2 msec. The latency of the abnormal muscle response obtained from the mentalis muscle in the model rats was about 7 msec. This value is close to the sum of the conduction time from the motonucleus to the mentalis muscle (2 msec) and the latency of the late response from the motonucleus (5 msec). Similar results were obtained in rats in which the facial nerve had been chronically stimulated electrically and which had developed an abnormal muscle response. The results of this study further support the hypothesis that the hyperactivity of the facial motonucleus is the pathophysiology of hemifacial spasm.

The abnormal muscle response, elicited by electrical stimulation of one branch of the facial nerve and recorded from muscles innervated by another branch, has been used previously as an objective sign of hemifacial spasm in the development of animal models of this disorder. In the present study we recorded spontaneous electromyographic activity from the orbicularis oculi muscle from both sides in rats in which a demyelination of the peripheral portion of the facial nerve and vascular contact had been made previously. The root mean square value of the electromyographic activity on the affected side was significantly larger than that on the unaffected side in all rats in which the vascular irritation had caused the abnormal muscle response to appear. The results support our earlier finding that vascular contact together with demyelination of the peripheral facial nerve can cause the development of signs of hemifacial spasm, including involuntary muscle contractions.

Recordings from the vicinity of the cochlear nucleus in 9 patients undergoing microvascular decompression operations to relieve hemifacial spasm, trigeminal neuralgia, tinnitus, and disabling positional vertigo were conducted by placing a monopolar electrode in the lateral recess of the fourth ventricle (through the foramen of Luschka), the floor of which is the dorsolateral surface of the dorsal cochlear nucleus. The click-evoked potentials recorded by such an electrode display a slow negative wave with a peak latency of about 6-7 msec on which several sharp peaks are superimposed. None of the peaks in the recordings from the vicinity of the cochlear nucleus coincided with any vertex-positive peaks of the brain-stem auditory evoked potentials. In recordings from the lateral aspect of the floor of the fourth ventricle near the cochlear nucleus 1 patient showed 2 positive peaks, the earliest of which had a latency close to that of peak II and the second of which had a latency close to the negative peak between peaks III and IV of the brain-stem auditory evoked potentials. There is a distinct negative peak in the responses recorded from the midline of the floor of the fourth ventricle, the latency of which is only slightly shorter than that of peak V of the brain-stem auditory evoked potentials, supporting earlier findings that the sharp tip of peak V of the brain-stem auditory evoked potentials is generated by the termination of the lateral lemniscus in the inferior colliculus.

The monitoring of auditory function by recording brain stem auditory evoked potentials in patients undergoing removal of acoustic tumors is hampered by the small amplitude of the brain stem auditory evoked potentials. Because several thousands of responses must be added, it takes several minutes to obtain an interpretable record. Recordings done directly from the exposed eighth nerve have much higher amplitudes, and, therefore, interpretable responses can be obtained after only a few responses have been added. However, it is difficult to place the recording electrode in an optimal position and the electrode may interfere with the removal of the tumor. In this report, we show that evoked potentials from the cochlear nucleus, which can be recorded by placing an electrode in the lateral recess of the fourth ventricle, have a large amplitude, and that the electrode placed in this way does not interfere with the removal of the tumor. This way of monitoring, therefore, yields interpretable responses within 15 to 20 seconds, or less, and makes it possible to detect injuries to the entire intracranial portion of the eighth nerve, just as brain stem auditory evoked potentials do, but 20 to 50 times faster.

Evoked spinal cord potentials (ESCPs) following transcranial magnetic stimulation werer recorded from the spinal cord in monkeys anesthetized with ketamine. Isopotential maps of the earlier negative deflection of the magnetic ESCP (N 1 wave) revealed a distribution of negative field potentials, the maximum of which were located within the medial dorsolateral funiculus, which corresponds to the dorsolateral corticospinal tracts. The N 1 wave of the magnetic ESCP had the same latency as the D-wave of the electrical ESCP elicited by either direct cortical or transcranial electrical stimulation. We assumed that the N 1 wave was generated by direct excitation of pyramidal axons. Isopotential maps of the waves that followed the N 1 peak (waves N 2 , N 3 , N 4 , and N 5 ) of the magnetic ESCP showed a negative field potential distribution, the maximum of which was at the ventromedial funiculus as well as within the medial dorsolateral funiculus. Later waves of magnetic ESCP were suggested to reflect not only the dorsal corticospinal tracts but also the ventromedial spinal cord function.

Not long ago, tinnitus and hyperacusis were considered intractable symptoms and the lack of interest and shortage of research in diseases with these symptoms would have made publishing a special issue on tinnitus and hyperacusis nearly impossible. During the past two decades, there has been an explosion of research on tinnitus and incremental growth on hyperacusis, a condition associated with hearing loss, autism, migraine, closed head injuries, Williams syndrome, fibromyalgia, and other sensory hypersensitivity disorders. Prior to 1980, a search of PubMed turned up fewer than 25 publications with tinnitus in the title (Figure 1); the situation for hyperacusis was even more dismal with less than 5 publications in 1980 and only 19 in 2014. Figure 1 A search of PubMed shows an exponential increase of publications related to tinnitus over the last 20 years, while research related to hyperacusis has been mainly overlooked. This increase in publications reflects a large increase in research made possible by new hypotheses about the pathology of these diseases, advances in neuroscience in general, and new technological approaches. The increase in research funding by private philanthropic organizations such as the American Tinnitus Association, the Tinnitus Research Consortium, the Tinnitus Research Initiative, and Action on Hearing Loss has been essential for the progress in understanding of tinnitus and hyperacusis and the treatment of these disorders. Research grants from governmental agencies have also contributed to these advances in research regarding tinnitus and hyperacusis. The incentive for this special issue was the tremendous personal, social, and financial costs associated with tinnitus and hyperacusis. For those suffering from severe or debilitating tinnitus or hyperacusis, the psychosocial and emotional costs can be enormous. While tinnitus and hyperacusis can affect anyone, young or old, those serving in the military are at a higher risk than nonmilitary people. Roughly 50% of combat personnel in the Gulf War developed tinnitus where exposure to intense noise and stress were likely the major contributing factors. Tinnitus ranks as the #1 service-connected disabilities in the Veterans Health Care System with compensation costs $1.2 billion for the year 2012, projected to reach $3 billion for the year 2017. The completion of this special issue is a testament to the tremendous efforts by research groups around the world to develop a better understanding of the neural mechanisms underlying tinnitus and hyperacusis and to develop better and more effective therapies. This special issue combines association studies (tinnitus and sleep, tinnitus and headaches, tinnitus and interoceptive awareness, mastoid pneumatization, and pulsatile tinnitus), diagnostic studies (how to measure hyperacusis, the relevance of high-frequency hearing loss in tinnitus), and treatment studies (coordinated reset acoustic stimulation, repeated rTMS sessions). A few highlights from the accepted papers in this special issue are discussed below. Hearing loss, which reduces the neural input to the central auditory system, is thought to be one of the major triggers for inducing tinnitus and aberrant neural activity within the brain; however, many people with tinnitus have normal hearing thresholds within the conventional audiometric range (0.25–8 kHz). The work of V. Vielsmeier et al. shows that many people with tinnitus who have what is regarded to be normal hearing have elevated hearing thresholds above 8 kHz, which are strongly correlated with the laterality of the tinnitus. The take home message is that high-frequency audiometry should be an integral part of a comprehensive tinnitus assessment. Some evidence suggests that the air spaces within the temporal bone (pneumatization) may contribute to the severity of pulsatile tinnitus. Using imaging techniques to quantify pneumatization, W. Liu et al., however, found little correlation between the severity of tinnitus and the degree of pneumatization. While many people with tinnitus have hearing loss, not everybody who has hearing loss has tinnitus, a result that supports other findings that show that tinnitus is a multifactorial disease. The article by B. Langguth et al. present evidence that tinnitus and headache may be pathologically linked, consistent with earlier research linking tinnitus and hyperacusis to migraine. Sleep disturbances are common in people with tinnitus but the relationship between sleep disturbance and the severity of a person's tinnitus has been unclear. M. Schecklmann et al. report that tinnitus distress is highly correlated with sleep disturbances. Over the past decade, many new and promising therapeutic approaches for treating tinnitus have emerged. Many different sound therapies designed to modify neural activity in the brain have been developed and remain to be validated. The exciting paper by C. Hauptmann et al. suggests that acoustic coordinated reset neuromodulation could become a therapeutic strategy for treating patients with chronic tonal tinnitus. Even though the lack of a control group does not permit showing real efficacy, the promising results of this open label study demonstrate that further controlled studies are warranted. Another approach to treating people with tinnitus is repetitive transcranial magnetic stimulation (rTMS). One of the main problems with published studies of the use of rTMS to treat people with tinnitus is the small effect size and the fact that the effect of rTMS in tinnitus is limited in time. In a paper in this issue A. Lehner et al. demonstrate that repeating the rTMS sessions seems to be beneficial when the tinnitus distress worsens after waning of the rTMS effect. The Hyperacusis Questionnaire is a tool used by clinicians to evaluate hyperacusis symptoms in tinnitus patients. Factor analysis of data obtained by K. Fackrell et al. suggests that only 10 items and two factors (attentional and social) in the Hyperacusis Questionnaire may be a more appropriate approach for assessing hyperacusis instead of the current 12 items and 3 factors (emotional, attentional, and social). Furthermore, it was shown by M. Schecklmann et al. that using only 2 questions can give a good hint at whether hyperacusis is present: (1) Do you have a problem tolerating sounds because they often seem much too loud? (2) Do sounds cause you pain or physical discomfort? P. Lau et al. demonstrate that tinnitus is unrelated to interoceptive awareness but that people with tinnitus tend to overestimate physical changes in comparison to people who do not have tinnitus. In summary, special issues like this, covering clinical, diagnostic, and treatment aspects of tinnitus and hyperacusis, remain highly needed to continue the quest for finding better and more effective ways to treat these elusive symptoms. Only a better understanding of the causes of both tinnitus and hyperacusis and their pathology can pave the way to reaching this goal. Aage R. Moller Richard Salvi Dirk De Ridder Tobias Kleinjung Sven Vanneste

The authors discuss the use of intraoperative monitoring of spinal cord function as an essential part of operations in which the spinal cord is at risk. Although early documented cases of intraoperative monitoring were during operations to correct spinal deformities such as scoliosis, intraoperative monitoring has also increased safety during other operations, such as tumor resection and arteriovenous malformation ablation.The authors highlight details involved in monitoring spinal cord function intraoperatively and discuss historical, current, and future perspectives on the use of these monitoring techniques as an essential part of operations in which the spinal cord is at risk.Intraoperative monitoring techniques mitigate the risk of post-operative deficits to the spinal cord by detecting injuries before they become permanent and while they can be reversed.Intraoperative spinal cord monitoring is safe, cost-effective, and valuable in reducing post-operative sensory and motor deficit. This technique should continue to be refined and its use consistently applied in any procedure where injury to the spinal cord is possible.

1. Both pain and tinnitus have many different forms. 2. Tinnitus and central neuropathic pain are phantom sensations similar to the phantom limb symptoms that occur without any physical stimulation of sensory receptors. 3. Tinnitus and neuropathic pain are typical examples of “plasticity disorders” where the symptoms are caused by plastic changes that are not beneficial to an individual person. 4. Central neuropathic pain and tinnitus have no physical signs. 5. The severity of pain and tinnitus are difficult to assess quantitatively even under laboratory circumstances. Only the patients’ own perception is a true measure of the severity of central pain and subjective tinnitus. 6. The perception of pain and tinnitus is affected by many factors such as actual circumstances, expectation, stress, and a person’s emotional state. 7. Many forms of pain are best described as suffering; the same is the case for severe subjective tinnitus. 8. Pain and tinnitus can have strong emotional components, it often prevents or disturbs sleep, and it can interfere with or prevent intellectual work. 9. It is difficult to get reliable data on epidemiology of tinnitus and central neuropathic pain because of their subjective nature and large variability. 10. Activation of neural plasticity is involved in causing and maintaining central neuropathic pain and many forms of subjective tinnitus. 11. The nervous system is the site of the anomalies that cause central neuropathic pain and many forms of tinnitus. Both tinnitus and pain involve a cascade of neural structures. 12. The pathology of the nervous system in some forms of central neuropathic pain is stable in the pathologic state. It may be similar for some forms of tinnitus. 13. Pain that is perceived as escapable uses a different part of the periaquaductal gray than pain that is perceived as inescapable. It is not known if tinnitus also has such distinctions. 14. Severe tinnitus is often accompanied by hyperacusis (lowered tolerance to sounds); pain may be accompanied by allodynia (pain from normally innocuous touch of the skin) hyperpathia (exaggerated reaction to acute pain), and hypersensitivity (lowered threshold for painful stimulation). 15. Some forms of tinnitus and pain can be modulated by electrical stimulation of the skin. 16. Electrical stimulation of several cortical structures can modulate both pain and tinnitus. 17. The sympathetic nervous system can modulate pain and some forms of tinnitus.

1. Subjective tinnitus has many forms and may be regarded as a group of disorders rather than a single disorder. 2. There are a few objective ways to distinguish between the different forms of tinnitus. 3. Tinnitus has been classified subjectively accor­ding to: (a) Intensity: Often using a visual analog scale or loudness matching. (b) Character: High frequency (like crickets), low frequency (rumbling), tonal, pulsatile, constant, or intermittent. (c) Other features such as the ability to modulate the tinnitus by manipulating their jaw, moving their eyes, or applying pressure on neck regions. (d) Whether referred to one ear, both ears, or perceived as being inside the head. 4. Some diseases, such as Meniere’s disease, are accompanied with tinnitus; such tinnitus may be different from other forms of tinnitus. 5. Some forms of tinnitus are associated with affective disorders such as depression or phonophobia. 6. Subjective tinnitus is often accompanied by abnormal perception of sounds, known as hyperacusis (lowered tolerance for sounds) or hypersensitivity to sounds.