Article

Burst stimulation of the auditory cortex: A new form of neurostimulation for noise-like tinnitus suppression: Clinical article

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Abstract

Tinnitus is an auditory phantom percept related to tonic and burst hyperactivity of the auditory system. Two parallel pathways supply auditory information to the cerebral cortex: the tonotopically organized lemniscal system, and the nontonotopic extralemniscal system, which fire in tonic and burst mode, respectively. Electrical cortex stimulation is a method capable of modulating activity of the human cortex by delivering stimuli in a tonic or burst way. Burst firing is shown to be more powerful in activating the cerebral cortex than tonic firing, and bursts may activate neurons that are not activated by tonic firing. Five patients with an implanted electrode on the auditory cortex were asked to rate their tinnitus distress and intensity on a visual analog scale before and after 40-Hz tonic and 40-Hz burst (5 pulses at 500 Hz) stimulation. All patients presented with both high-pitched pure tone and white noise components in their tinnitus. A significantly better suppression for narrowband noise tinnitus with burst stimulation in comparison with tonic stimulation (Z = -2.03, p = 0.04) was found. For pure tone tinnitus, no difference was found between tonic and burst stimulation (Z = -0.58, p = 0.56). No significant effect was obtained for stimulation amplitude (Z = -1.21, p = 0.23) and electrical charge per pulse (Z = -0.67, p = 0.50) between tonic and burst stimulation. The electrical current delivery per second was significantly different (Z = -2.02, p = 0.04). Burst stimulation is a new form of neurostimulation that might be helpful in treating symptoms that are intractable to conventional tonic stimulation. Further exploration of this new stimulation design is warranted.

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... To investigate the differential effect of burst stimulation compared with tonic stimulation, implanted tinnitus patients presenting intractable tinnitus to tonic stimulation were subsequently investigated by using burst auditory cortex stimulation (De Ridder et al., 2010b). Applying burst stimulation generated improvement for 48% of the tinnitus patients who did not respond to tonic stimulation (De Ridder et al., 2011b). ...
... Therefore, adding burst stimulation improves auditory cortex stimulation for tinnitus from a poor response rate to an acceptable, though far from ideal, suppression rate (De Ridder et al., 2011b). Burst stimulation seems especially beneficial for patients with difficult-to-treat noiselike tinnitus (De Ridder et al., 2010b, 2011b. ...
... The unique feature of burst technology is related to its fundamental aspect of mimicking nature, more specifically the burst firing pattern that exists in our nervous system from the periphery, to the autonomic nervous system, to the spinal cord, all the way up to the brain, both in the reward system and in the thalamocortical columns. By providing stimulation in a physiologic manner, burst stimulation permits paresthesia-free SCS (De Ridder et al., 2010b). Indeed, there is no reason why, in a physiologic way, paresthesia would have to be required to obtain pain suppression, as is the case with tonic stimulation (North et al., 1991). ...
... In summary, nine studies were evaluated "poor" and were determined to have a potentially significant risk of bias (34,35,(40)(41)(42)(43)(45)(46)(47). Nine studies were classified as "fair" quality (44,(48)(49)(50)(51)(52)(53)(54)(55), and two studies had a "good" quality according to our evaluation (56,57). Only one included study was evaluated as "excellent" (58). ...
... Most of the included studies in this review examined the effect of cortical stimulation on tinnitus. In the studies by De Ridder and colleagues (47,50,52), patients were selected based on responsiveness (tinnitus suppression of at least 20-50%) to noninvasive TMS therapy. In these patients, extradural tonic stimulation of the auditory cortex resulted in a significant improvement (measured by VAS scales, see Table 1) of the tonal tinnitus, while burst stimulation resulted in an improvement of both the tonal type and the white noise type of tinnitus (50). ...
... In the studies by De Ridder and colleagues (47,50,52), patients were selected based on responsiveness (tinnitus suppression of at least 20-50%) to noninvasive TMS therapy. In these patients, extradural tonic stimulation of the auditory cortex resulted in a significant improvement (measured by VAS scales, see Table 1) of the tonal tinnitus, while burst stimulation resulted in an improvement of both the tonal type and the white noise type of tinnitus (50). Overall, patients with pure tone tinnitus yielded better results (reduction of VAS score by 8 points [n = 2] vs. by 2 points in white noise tinnitus [n = 5]) (47). ...
Article
Objective: Although the prevalence and burden of tinnitus is high, none of the available tinnitus treatments has been proven to be effective for the majority of tinnitus patients so far. Neuromodulation is currently gaining more interest to explore as tinnitus treatment. Because noninvasive neuromodulation has been shown to be effective in some tinnitus patients in the short term, more invasive techniques have been applied with variable success and without clear clinical applicability. As new insights into the neuropathophysiology of tinnitus arise, it seems essential to recapitulate the current evidence of invasive neuromodulation for tinnitus, to assess the quality of the available studies and identify gaps in this research domain. Data Sources: MEDLINE, Embase, Web of Science and Clinical Trial Register. Materials and Methods: We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Studies since 2005 that reported on adult human subjects with chronic subjective tinnitus, who underwent some form of invasive neuromodulation, were included. Quality evaluation was performed using the modified Downs and Black checklist. Results and Conclusion: Twenty-one studies were included. Studies were often of low quality due to low sample sizes, lack of controlled designs, or investigating tinnitus as a secondary indication of neuromodulation. Current research results provide insufficient evidence to generally recommend invasive neuromodulation as an alternative treatment alternative for intractable tinnitus, although some promising effects are mentioned. Further research must be encouraged to gain more insight in this treatment including optimization of the technique, and standardization of tinnitus evaluation in subgroups. Keywords: Cortical stimulation, deep brain stimulation, invasive neuromodulation, review, tinnitus
... BurstDR TM stimulation was developed in 2010 [7,8] by mimicking physiological burst firing in the thalamus [9]. The initial development and research was for tinnitus suppression, targeting the auditory cortex [8,10]. ...
... BurstDR TM stimulation was developed in 2010 [7,8] by mimicking physiological burst firing in the thalamus [9]. The initial development and research was for tinnitus suppression, targeting the auditory cortex [8,10]. After 5 randomized controlled trials [11,12] including 4 placebo-controlled trials [13][14][15][16] a large non-inferiority study was performed in the USA to obtain FDA approval for burstDR TM spinal cord stimulation [17]. ...
... Recently burstDR TM stimulation has also been used in the cervical spinal cord for gait and cognitive improvement in Parkinson's disease [24,25], as well as for essential [26] and orthostatic [27] tremor. In almost all of the above studies burstDR TM stimulation was superior to classical tonic stimulation [7,8,[10][11][12]14,17,19,23,[26][27][28], which can likely be explained by its physiological action. ...
Article
Introduction: Since the introduction of burst spinal cord stimulation for neuropathic pain, several companies have developed their own version of burst stimulation, which is confusing the marketplace and clinicians of what burst stimulation truly is, the value and utilization of the therapy. Areas covered: We review those two burst stimulation designs and notice important differences. The original burstDRTM stimulation tries to mimic physiologic burst firing, which involves closely spaced high frequency sodium spikes nested on a calcium mediated plateau. This is realized by generating a train of 5 monophasic spikes of increasing amplitude with passive charge balance after the last spike, in contrast to the other burst designs which involve a version of cycling 4-5 spikes each being individually actively charge balanced spikes. Expert opinion: Based on the neurobiology of burst firing as well as abductive reasoning we like to clarify that burstDRTM is a true physiologic burst stimulation, and that other versions being called burst stimulation are essentially clustered tonic stimulation. This differentiating terminology will prevent confusion for healthcare providers, regulators, and the marketplace of what burst stimulation is.
... BurstDR TM stimulation was developed in 2010 [7,8] by mimicking physiological burst firing in the thalamus [9]. The initial development and research was for tinnitus suppression, targeting the auditory cortex [8,10]. ...
... BurstDR TM stimulation was developed in 2010 [7,8] by mimicking physiological burst firing in the thalamus [9]. The initial development and research was for tinnitus suppression, targeting the auditory cortex [8,10]. After 5 randomized controlled trials [11,12] including 4 placebo-controlled trials [13][14][15][16] a large non-inferiority study was performed in the USA to obtain FDA approval for burstDR TM spinal cord stimulation [17]. ...
... Recently burstDR TM stimulation has also been used in the cervical spinal cord for gait and cognitive improvement in Parkinson's disease [24,25], as well as for essential [26] and orthostatic [27] tremor. In almost all of the above studies burstDR TM stimulation was superior to classical tonic stimulation [7,8,[10][11][12]14,17,19,23,[26][27][28], which can likely be explained by its physiological action. ...
Article
Introduction: Since the introduction of burst spinal cord stimulation for neuropathic pain, several companies have developed their own version of burst stimulation, which is confusing the marketplace and clinicians of what burst stimulation truly is, the value and utilization of the therapy. Areas covered: We review those two burst stimulation designs and notice important differences. The original burstDRTM stimulation tries to mimic physiologic burst firing, which involves closely spaced high frequency sodium spikes nested on a calcium mediated plateau. This is realized by generating a train of 5 monophasic spikes of increasing amplitude with passive charge balance after the last spike, in contrast to the other burst designs which involve a version of cycling 4-5 spikes each being individually actively charge balanced spikes. Expert opinion: Based on the neurobiology of burst firing as well as abductive reasoning we like to clarify that burstDRTM is a true physiologic burst stimulation, and that other versions being called burst stimulation are essentially clustered tonic stimulation. This differentiating terminology will prevent confusion for healthcare providers, regulators, and the marketplace of what burst stimulation is.
... The same holds for tinnitus. Whereas in most studies the electrodes are implanted extradurally or intradurally overlying the primary or secondary auditory cortex respectively (16)(17)(18)(19)(20)(21)(22)(23)(24), some patients have been treated with wire electrodes implanted inside the auditory cortex (25). We will consider any form of cortical stimulation, whether intracortical or onto the cortex, as cortical stimulation, and deep brain stimulation as specifically targeting deep nuclei, rather than cortical structures. ...
... Tinnitus is a prevalent symptom, with clinical, pathophysiological, and treatment features analogous to pain. Invasive auditory cortex stimulation (iACS) via implanted electrodes onto or into the primary auditory cortex (inside the posterior part of the Sylvian valley) or overlying the secondary auditory cortex (posterior part of the superior temporal gyrus) have been developed to treat severe cases of intractable tinnitus (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)50). ...
... Average tinnitus reduction is 53% for the entire group, but frequent reprogramming or multiprogram stimulation is required in many patients to maintain beneficial results, as habituation to the stimulation seems to occur almost universally (50), similarly to what is described for motor cortex stimulation for pain. Burst stimulation is capable of suppressing tinnitus in more patients more effectively than tonic stimulation, especially for noise-like tinnitus (22). For pure tone tinnitus, there are no differences between the two stimulation designs. ...
Article
Objective: Electrical stimulation via implanted electrodes that overlie the cortex of the brain is an upcoming neurosurgical technique that was hindered for a long time by insufficient knowledge of how the brain functions in a dynamic, physiological, and pathological way, as well as by technological limitations of the implantable stimulation devices. Methods: This paper provides an overview of cortex stimulation via implantable devices and introduces future possibilities to improve cortex stimulation. Results: Cortex stimulation was initially used preoperatively as a technique to localize functions in the brain and only later evolved into a treatment technique. It was first used for pain, but more recently a multitude of pathologies are being targeted by cortex stimulation. These disorders are being treated by stimulating different cortical areas of the brain. Risks and complications are essentially similar to those related to deep brain stimulation and predominantly include haemorrhage, seizures, infection, and hardware failures. For cortex stimulation to fully mature, further technological development is required to predict its outcomes and improve stimulation designs. This includes the development of network science-based functional connectivity approaches, genetic analyses, development of navigated high definition transcranial alternating current stimulation, and development of pseudorandom stimulation designs for preventing habituation. Conclusion: In conclusion, cortex stimulation is a nascent but very promising approach to treating a variety of diseases, but requires further technological development for predicting outcomes, such as network science based functional connectivity approaches, genetic analyses, development of navigated transcranial electrical stimulation, and development of pseudorandom stimulation designs for preventing habituation.
... On the second postoperative day, once craving set in, the electrodes were activated with a custom-made programmer in 3-Hz burst mode, consisting of 5 spikes at 500-Hz spike mode, with a 1000-microsecond pulse width and an amplitude of 1.5 mA. 32,33 The electrode pole configuration was 12121212 to generate a large stimulation field. The amplitude was titrated to craving reduction. ...
... The burst stimulation design used here for suppressing dACC/ SMA activity has been recently developed 33 and has been used in the brain 32 and on the spinal cord 42 and peripheral nerves. 43 It tries to mimic burst firing in the brain, is a stronger activator of the postsynaptic potential, whether excitatory 44,45 or inhibitory, 46 and appears to be clinically more effective than tonic stimulation. ...
... 43 It tries to mimic burst firing in the brain, is a stronger activator of the postsynaptic potential, whether excitatory 44,45 or inhibitory, 46 and appears to be clinically more effective than tonic stimulation. 32,33,42,43,47 The 500-Hz spike mode in burst firing elicits the greatest inhibitory postsynaptic potential 46 and is therefore selected. Low-frequency stimulation (1 Hz, 90 mA, 200 microseconds) at the anterior cingulate cortex inhibits its activity and has behavioral effects in primates. ...
Article
BACKGROUND AND IMPORTANCE Alcohol dependence is related to dysfunctional brain processes, in which a genetic background and environmental factors shape brain mechanisms involved with alcohol consumption. Craving, a major component determining relapses in alcohol abuse, has been linked to abnormal brain activity. CLINICAL PRESENTATION We report the results of a treatment-intractable, alcohol-addicted patient with associated agoraphobia and anxiety. Functional imaging studies consisting of functional magnetic resonance imaging and resting-state electroencephalogram were performed as a means to localize craving-related brain activation and for identification of a target for repetitive transcranial magnetic stimulation and implant insertion. Repetitive transcranial magnetic stimulation of the dorsal anterior cingulate cortex with a double-cone coil transiently suppressed his very severe alcohol craving for up to 6 weeks. For ongoing stimulation, 2 “back-to-back” paddle electrodes were implanted with functional magnetic resonance imaging neuronavigation guidance for bilateral dorsal anterior cingulate cortex stimulation. Using a recently developed novel stimulation design, burst stimulation, a quick improvement was obtained on craving, agoraphobia, and associated anxiety without the expected withdrawal symptoms. The patient has remained free of alcohol intake and relieved of agoraphobia and anxiety for over 18 months, associated with normalization of his alpha and beta activity on electroencephalogram in the stimulated area. He perceives a mental freedom by not being constantly focused on alcohol. CONCLUSION This case report proposes a new pathophysiology-based target for the surgical treatment of alcohol dependence and suggests that larger studies are warranted to explore this potentially promising avenue for the treatment of intractable alcohol dependence with or without anxiety and agoraphobia.
... This gap in new neuropharmacological developments can be filled in by out-licensing [28] and by the development of new stimulation approaches. An example is the development of burst stimulation, which was originally developed for tinnitus suppression by auditory cortex stimulation [27,29], and later translated to the spinal cord for pain, as well as to the peripheral nervous system for pain and tinnitus, [30,31] and is now being tested for anterior cingulate stimulation in the treatment of alcohol addiction (https://www.anzctr.org.au/Trial/Registration/ TrialReview.aspx?id=366816). ...
... With the recent development of new stimulation designs such as burst stimulation [16][17][18]29] and high-frequency stimulation [14,15], it is clear that improvement of clinical results is not only to be found by better targeting or better coverage of paresthesias, but by the development of new stimulation designs that can tune therapy to a patient's individual condition. This will require the development of adjustable or upgradable IPGs, which will mimic the current evolution in smartphones, tablets, etc., in other words, a generic open-platform hardware will be required on which new stimulation designs can be downloaded, analogous to apps for smartphones. ...
... The Proclaim and the Protégé are the first real upgradable stimulator/IPGs, and set the tone for the future in developing medical devices for SCS and beyond. It is highly likely that DBS, cortex stimulation, and peripheral nerve stimulation, as well as DRG stimulation, will also benefit from this upgradable approach, as for example burst stimulation is also beneficial for cortex stimulation, both somatosensory cortex [66], auditory cortex [29], cingulate cortex [67] and peripheral nerve stimulation [30,31], and there is no reason to a priori believe the same rationale will not be applicable for DBS and DRG stimulation. The future is upgradeable. ...
Article
Recently burst stimulation and 10 kHz stimulation have been developed as novel stimulation designs. Both appear to be superior to classical tonic stimulation in the amount of responders and the amount of pain suppression and have as an extra advantage that they are paresthesia-free. This evolution is very important as it shifts the focus of research from better targeting by developing new lead configurations to better communication with the nervous system. It can be envisioned that this is only the start of a new trend in spinal cord, brain, and peripheral nerve stimulation and that more novel stimulation designs will be developed in the near future such as pseudorandom burst stimulation, pleasure stimulation, noise stimulation and reconditioning stimulation. This evolution mandates a novel approach in the development of internal pulse generators, and the most obvious approach is to develop an upgradable stimulator, on which novel stimulation designs can be downloaded, analogous to the apps people download on their smartphones. This will create a shift from hardware driven products to software driven stimulators.
... The burst firing is able to overdrive ongoing tonic firing. 22 Burst auditory cortex stimulation has been applied in tinnitus patients with better effect on noise-like tinnitus than with tonic stimulation. 23 In the literature there is one case report on the effects of burst MCS in chronic pain. ...
... 23 Initially burst stimulation has been applied on auditory cortex to suppress tinnitus more effectively than tonic stimulation. 22,38 De Ridder was the first who reported improvement in trigeminal anesthesia dolorosa after somatosensory cortex stimulation with burst mode, but also to the anterior cingulate cortex and dorsolateral, prefrontal cortex. 24 Finally, burst stimulation has been developed for spinal cord stimulation. ...
Article
Full-text available
Background: Motor cortex stimulation (MCS) is an intracranial, invasive method for treatment of chronic pain. Main indications for MCS are central post stroke pain, neuropathic facial pain, phantom limb pain and brachial plexus or spinal cord injury pain. Spinal cord stimulation (SCS) with burst waveform has been proved to be more effective than tonic mode in chronic pain. Necessity to replace depleted batteries of motor cortex tonic stimulators gave us an opportunity of applying burst stimulation. The objective of the pilot study was to evaluate the effects of burst stimulation applied on motor cortex in patients with chronic pain syndromes as well as comparison to tonic mode. Materials and methods: We have evaluated 6 patients (females N=3, males N=3) belonging to the group of 14 cases (females N=5, males N=9) who had undergone surgical procedure of MCS in years 2005-2017. Selected for the study were 6 patients with thalamic pain N=3, with facial pain N=3 (anaesthesia dolorosa and neuropathic trigeminal neuralgia). The patients were subjected to both modes of stimulation then they chose which one was better in relieving pain: tonic or burst. Pain intensity was assessed with the visual analogue scale (VAS) before the replacement of implanted pulse generator (IPG) and after the stimulation with tonic and burst modes. Results: In the study, 5 out of 6 patients with MCS found burst mode more effective than tonic mode. Baseline VAS score in patients that had at least 3 months depleted battery of tonic IPG was 95 mm. After implantation of a new IPG mean VAS score on tonic stimulation was 72 mm, on burst 53 mm. Conclusions: The most preferred option of MCS in selected group of patients was burst stimulation. This study has shown, that the burst stimulation of cerebral cortex is a promising modality when tonic stimulation is not sufficient in refractory, neuropathic pain.
... This results in a complete suppression of the pure tone component of the tinnitus, but the noise-like component is less successfully suppressed. Whereas initially his noise-like tinnitus is reduced from 8 to 4/10, the noise-like phantom sound remains and worsens again to 6/10 both for loudness and distress, even after changing the stimulation design to burst stimulation, which is better in suppressing noise-like tinnitus than tonic stimulation [20,22]. ...
... However, it has been shown that noise-like tinnitus is resistant to auditory cortex stimulation with tonic stimuli, both in transcranial magnetic stimulation [15,16] and with implanted electrodes [11]. His tinnitus cannot be suppressed, even by burst stimulation, which has been developed to specifically treat noise-like tinnitus [20,22]. ...
... After 4 weeks, his stimulation design was altered to verify if further improvement could be obtained. A recently developed stimulation design consisting of a 6-Hz burst mode, 5 spikes at a 500-Hz spike mode, and a 1000-μsec pulse width at 1.4 mA 15,16 was used in an attempt to improve his clinical picture. Burst stimulation was provided by an Eon implantable pulse generator (St. ...
... All episodic artifacts were removed from the stream of the EEG. Average Fourier cross-spectral matrices were computed for bands delta (2-3.5 Hz), theta (4-7.5 Hz), alpha (8)(9)(10)(11)(12), beta (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and gamma . ...
Article
Tinnitus can be distressful, and tinnitus distress has been linked to increased beta oscillatory activity in the dorsal anterior cingulate cortex (dACC). The amount of distress is linked to alpha activity in the medial temporal lobe (amygdala and parahippocampal area), as well as the subgenual (sg)ACC and insula, and the functional connectivity between the parahippocampal area and the sgACC at 10 and 11.5 Hz. The authors describe 2 patients with very severely distressing intractable tinnitus who underwent transcranial magnetic stimulation (TMS) with a double-cone coil targeting the dACC and subsequent implantation of electrodes on the dACC. One of the patients responded to the implant and one did not, even though phenomenologically they both expressed the same tinnitus loudness and distress. The responder has remained dramatically improved for more than 2 years with 6-Hz burst stimulation of the dACC. The 2 patients differed in functional connectivity between the area of the implant and a tinnitus network consisting of the parahippocampal area as well as the sgACC and insula; that is, the responder had increased functional connectivity between these areas, whereas the nonresponder had decreased functional connectivity between these areas. Only the patient with increased functional connectivity linked to the target area of repetitive TMS or implantation might transmit the stimulation current to the entire tinnitus network and thus clinically improve.
... One approach to circumvent the difficulty of the selection of control groups is to include only people whose tinnitus loudness can be influenced by eye movements 103 , jaw movements 104 , injection of intravenous lidocaine 105 , transcranial stimulation 106 or epidural stimulation with implanted electrodes 107 . However, such studies have two inherent limitations: first, they include only a specific subgroup that may not be representative of the entire tinnitus spectrum, and second, the intervention under investigation may have neuronal effects unrelated to the effect on tinnitus. ...
... On the other hand, for somatosensory cortex stimulation to treat neuropathic pain, 4 to 8 Hz burst mode with 500 Hz spike mode is used (54). For the auditory cortex stimulation in the treatment of tinnitus, different burst frequencies are being used (55,56), whereas for dorsolateral prefrontal cortex stimulation in the treatment of tinnitus, 22 Hz (harmonics of 11 Hz, which was the patient's individual alpha frequency) empirically yielded the best result (57). Ultimately, the goal is to mimic natural and physiological burst firing by adjusting programming to the target tissue. ...
Article
Objective: Spinal cord stimulation is commonly used to treat medically intractable pain. Different stimulation designs are used to obtain pain suppression such as tonic stimulation, high frequency stimulation, and burst stimulation. Preliminary analysis of the same data used in this study demonstrated that burst stimulation likely modulates the medial pain pathways in contrast to tonic stimulation. The question arises what different and common supraspinal mechanisms burst and tonic stimulation use. Materials and methods: The clinical and electroencephalography (EEG) data of five patients undergoing tonic, burst, and sham stimulation were analyzed to look at the commonalities and differences between burst and tonic stimulation. A source-localized (sLORETA) EEG substraction and conjunction analysis is performed in each condition for both activity and functional connectivity. A ratio between the dorsal anterior cingulate cortex (dACC) and pregenual anterior cingulate cortex/ventromedial prefrontal cortex (pgACC/vmPFC) is calculated to reflect a balance between pain supporting and pain suppressing systems. Results: Differences are noted in the dACC, dorsolateral prefrontal cortex, the primary somatosensory cortex, and the posterior cingulate cortex (PCC). Burst and tonic stimulation share activation in the pgACC, inferior parietal area, which encompasses the inferior secondary somatosensory cortex, PCC, and the parahippocampus. Burst suppression normalizes the pain supporting/pain suppressing balance in contrast to tonic stimulation. Discussion and conclusion: These data suggest that burst and tonic stimulation both modulate the descending pain inhibitory system (via pgACC), as well as a self-referential contextual (via PCC) aversive memory system (via parahippocampus). However, burst normalizes the pain supporting/suppressing balance in contrast to tonic mode by a greater effect on the dACC.
... A second waveform being studied is a "burst" pattern. This has arbitrarily been chosen as a series of five 1000 ms pulses at a pulse frequency 500 Hz followed by a single repolarization pulse, with each train repeated at 40 Hz (19,62). Burst stimulation is proposed to provide a signal that is more similar and relevant to endogenous activation patterns in the nervous system. ...
Article
Objective: All spinal cord stimulation (SCS) parameters (amplitude, pulse width, frequency) influence the interaction of stimulation with the nervous system and impact the delivery of charge. Regardless of the stimulation pattern, there are certain crucial elements related to dose, and a basic fundamental knowledge of the parameters used to administer the therapy is fundamentally important. Methods: This paper reviews basic concepts of energy delivery in neurostimulation (amplitude, pulse width, and frequency) and introduces the concept of the duty cycle and charge per sec as another way to characterize stimulation patterns. Results: Results from recent clinical publications indicate that an important aspect of the therapy may be the total charge delivery over a period of time. Viewed in this way, rate of charge delivery may be analogous to dosage of medication, and SCS parameters that use different duty cycles may exert distinct therapeutic effects by allowing different amounts of energy to be delivered to neural tissue with less sensory percept or even none at all. Conclusions: The basic parameters of amplitude, pulse width, and frequency have important implications for the delivery of charge in SCS. Modern programming strategies require an understanding of charge delivery for conventional SCS therapy as well as new therapies such as 10 kHz and burst SCS.
... One approach to circumvent the difficulty of the selection of control groups is to include only people whose tinnitus loudness can be influenced by eye movements 103 , jaw movements 104 , injection of intravenous lidocaine 105 , transcranial stimulation 106 or epidural stimulation with implanted electrodes 107 . However, such studies have two inherent limitations: first, they include only a specific subgroup that may not be representative of the entire tinnitus spectrum, and second, the intervention under investigation may have neuronal effects unrelated to the effect on tinnitus. ...
Article
Full-text available
Tinnitus is the perception of phantom sound in the absence of a corresponding external source. It is a highly prevalent disorder, and most cases are caused by cochlear injury that leads to peripheral deafferentation, which results in adaptive changes in the CNS. In this article we critically assess the recent neuroimaging studies in individuals with tinnitus that suggest that the disorder is accompanied by functional and structural brain abnormalities in distributed auditory and non-auditory brain regions. Moreover, we consider how the identification of the neuronal mechanisms underlying the different forms of tinnitus would benefit from larger studies, replication and comprehensive clinical assessment of patients.
... The monophasic pulses are charge balanced at the end of the burst, differentiating it from clustered high frequency tonic stimulation. It was initially developed for auditory cortex stimulation as a treatment for noise-like tinnitus, which did not respond to classical tonic auditory cortex stimulation (24). The underlying philosophy was that noise-like tinnitus was generated by hyperactive burst firing in the nontonotopic (hence noiselike sound perception) extralemniscal auditory system and that suppressing hyperactive burst firing requires a more powerful stimulation than tonic stimulation (25). ...
Article
Background: Spinal cord stimulation (SCS) is routinely used for intractable pain syndromes. For SCS to be efficacious the painful area needs to be covered by SCS induced paresthesia symptoms. Recently, novel stimulation designs have been developed for spinal cord stimulation (SCS) that are superior to classical spinal cord stimulation and exert their effects without the mandatory paresthesia. Two such stimulation designs are burst stimulation and 10 kHz stimulation. Objective: Whereas the mechanism of action of burst SCS has been partly elucidated, in that it modulates the medial pain pathway in contrast to tonic stimulation, the mechanism of action of 10 kHz SCS is still enigmatic. The goal of this paper is to provide a perspective or informed opinion on the differences and similarities between burst SCS and 10 kHz stimulation by using a literature search on the two stimulation designs. Discussion/conclusion: Human clinical data, simulation studies, quantitative sensory testing, cellular investigations, and comparative animal and human studies all point in the same direction, namely that 10 kHz and burst SCS might both modulate the medial pain pathway, and could be fundamentally similar neurostimulation designs.
... Burst SCS is a biomimetic, low-energy stimulation paradigm in which a short pulse train of high-frequency spikes (internal frequency 500 Hz) are delivered at 40 Hz [32,63,64]. Burst stimulation was initially used to treat noise-like tinnitus [68][69][70] and then was translated to modulate pain pathways, in which it was noted that burst stimulation was efficacious not only in modulating discriminatory aspects of pain, but in the affective response to pain as well [24]. Furthermore, burst SCS does not evoke paresthesias, allowing for placebo-controlled studies for comparison with tonic stimulation [64]. ...
Article
Full-text available
Objective: This is a comprehensive, structured review synthesizing and summarizing the current experimental data and knowledge about the mechanisms of action (MOA) underlying spinal cord stimulation with the burst waveform (as defined by De Ridder) in chronic pain treatment. Methods: Multiple database queries and article back-searches were conducted to identify the relevant literature and experimental findings for results integration and interpretation. Data from recent peer-reviewed conference presentations were also included for completeness and to ensure that the most up-to-date scientific information was incorporated. Both human and animal data were targeted in the search to provide a translational approach in understanding the clinical relevance of the basic science findings. Results/conclusions: Burst spinal cord stimulation likely provides pain relief via multiple mechanisms at the level of both the spinal cord and the brain. The specific waveforms and temporal patterns of stimulation both play a role in the responses observed. Differential modulation of neurons in the dorsal horn and dorsal column nuclei are the spinal underpinnings of paresthesia-free analgesia. The burst stimulation pattern also produces different patterns of activation within the brain when compared with tonic stimulation. The latter may have implications for not only the somatic components of chronic pain but also the lateral and affective pathway dimensions as well.
... The resurgence is based on the concept that novel functional and structural brain imaging data can pinpoint where and how in the brain dysfunctions arise that can be remediated by very specific neuromodulation interventions. This coincides with the development of new stimulation designs (8)(9)(10), that is, new ways to electrically manipulate the brain that seem to be more powerful and more selective in modifying individual behavior (11) in comparison to classical neurostimulation designs. Some of the new stimulation designs mimic nature by copying the physiological responses of the brain, which seems to be adaptively more successful in animals (12) and humans (13). ...
Article
Objective: A definition of free will is the ability to select for or against a course of action to fulfill a desire, without extrinsic or intrinsic constraints that compel the choice. Free will has been linked to the evolutionary development of flexible decision making. In order to develop flexibility in thoughts and behavioral responses, learning mechanisms have evolved as a modification of reflexive behavioral strategies. The ultimate goal of the brain is to reduce uncertainty inherently present in a changing environment. A way to reduce the uncertainty, which is encoded by the rostral anterior cingulate, is to make multiple predictions about the environment which are updated in parallel by sensory inputs. The prediction/behavioral strategy that fits the sensory input best is then selected, becomes the next percept/behavioral strategy, and is stored as a basis for future predictions. Acceptance of predictions (positive feedback) is mediated via the accumbens, and switching to other predictions by the dorsal anterior cingulate cortex (ACC) (negative feedback). Maintenance of a prediction is encoded by the pregenual ACC. Different cingulate territories are involved in rejection, acceptance and maintenance of predictions. Free will is known to be decreased in multiple psychopathologies, including obsessive compulsive disorder and addictions. Methodology: In modern psychosurgery three target structures exist for obsessive compulsive disorder and addiction: the dorsal ACC, the nucleus accumbens, and/or the anterior limb of the internal capsula. Research in all three areas reports favorable results with acceptable side effects. Psychosurgical interventions seem to exert their effect by a common final common pathway mediated via the pregenual ACC. Conclusion: Successful neuromodulation increases the capacity to choose from different options for the affected individual, as well as inhibiting unwanted options, therefore increasing free will and free won't.
... Secondly, we observed that there was a significantly more pronounced effect of high-frequency stimulation in patients perceiving PT tinnitus compared to those with NBN, while no preference for PT or NBN could be demonstrated with lf-tRNS. Previously, it has been revealed that noise-like tinnitus can best be suppressed by burst TMS (De Ridder et al. 2007b) and burst electrical stimulation (De Ridder et al. 2010), while PT tinnitus can equipotentially be suppressed by tonic and burst stimulation (De Ridder et al. 2007b). An effect that can be explained by the differences in the underlying neurophysiological mechanism of PT and NBN tinnitus as it has been suggested that NBN might be the result of increased burst firing in the extralemniscal/non-tonotopic pathway, which projects to the secondary auditory cortex and association cortices, while PT tinnitus might be caused by increased tonic firing of the lemniscal/tonotopic system, which projects to the primary auditory cortex (De Ridder et al. 2007b). ...
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Tinnitus is the sensation of a ringing, buzzing, roaring or hissing sound in the absence of an external sound. As tinnitus has been related to hyperactivity and synaptic plasticity changes in the central auditory system, invasive and noninvasive neuromodulation methods have been used to interfere with this underlying mechanism to reduce tinnitus loudness and distress. Recently, transcranial random noise stimulation applied over the auditory cortex induced a more pronounced effect on tinnitus loudness than transcranial direct current and alternating current stimulation. We performed tRNS over the temporoparietal cortex in 154 patients with non-pulsatile tinnitus. A total of 119 patients received low-frequency tRNS (lf-tRNS), 19 high-frequency tRNS (hf-tRNS) and 16 whole frequency spectrum tRNS (wf-tRNS). The effect was evaluated by using the numeric rating scale loudness and distress pre- and post-stimulation. This study revealed a significant reduction in tinnitus loudness when lf-tRNS and hf-tRNS were applied as well as a reduction in tinnitus-related distress with lf-tRNS. Moreover, we observed a significantly more pronounced reduction in loudness and distress in pure tone (PT) tinnitus compared to narrow band noise (NBN) tinnitus when hf-tRNS was applied, a difference that could not be obtained with lf-tRNS. Based on these results, tRNS might be a promising treatment option for non-pulsatile tinnitus; however, we cannot yet provide a clear mechanistic explanation for the different results obtained with different types of stimulation, i.e., lf-tRNS, hf-tRNS and wf-tRNS, or with different types of tinnitus, i.e., PT and NBN tinnitus.
... This stimulation design is characterized by a 5-pulse train with internal frequency of 500 Hz delivered at 40 Hz, with a 1 ms pulse width, utilizing a passive recharge pattern. Since its first use to treat tinnitus over a decade ago [9], more than 15 studies have demonstrated the effectiveness of passive recharge burst SCS (hereafter referred to as B-SCS) in a chronic pain population, including 5 Level 1 evidence studies showing superiority compared with conventional tonic stimulation for back and leg pain [10][11][12][13][14]. B-SCS is United States Food and Drug Administration (FDA) approved for patients with chronic pain. ...
Article
Background context Psychological characteristics such as catastrophizing and depression have been shown to negatively impact outcome prognosis after spinal interventions. Purpose To evaluate whether high psychological distress, defined as clinically elevated levels of catastrophizing and depression, is associated with poorer outcomes after spinal cord stimulation utilizing a passive recharge burst stimulation design. This proprietary waveform may uniquely attenuate the emotional aspects of chronic pain given its affects on the medial pain pathway projecting to the dorsal anterior cingulate cortex and anterior insula. Study Design/Settings Data were extracted from the prospective, multi-center, single-arm, international TRIUMPH study. The purpose of TRIUMPH was to assess long-term (2 years) safety and effectiveness of spinal cord stimulation for chronic pain in the trunk and/or limbs using a passive recharge enabled burst spinal cord stimulation (B-SCS) system. Patient Sample Two subsets of study patients were identified; those with (n=31) and those without (n=54) high psychological distress. Outcome Measures Psychological and functional outcomes as well as pain intensity and impact of pain on life were administered at baseline and all follow intervals. Additionally, patient satisfaction and patient global impression of change were assessed at all follow-up intervals. Methods Psychological distress (PD) was defined as a baseline score of ≥ 30 on the Pain Catastrophizing Scale (PCS) and ≥ 10 on the Patient Health Questionnaire Depression scale (PHQ-9). Non-distressed (ND) patients had scores below these thresholds on both scales. All patients were implanted with a B-SCS system and completed data collection for the 24-month follow-up visit. This study was funded by Abbott. JMH is a consultant for Abbott and has received <$20,000 in lifetime consulting fees from Abbott. SMF is a consultant for Abbott and has received >$50,000 in lifetime consulting fees from Abbott. BB is an Abbott employee. RAC is a former Abbott employee. JJY is a consultant for Abbott and has received <$2,500 in lifetime consulting fees from Abbott. Results Of the 128 participants with 24-month data, 31 (24%) and 54 (35%) met the criteria for PD and ND, respectively. Baseline measures indicated a more severe chronic pain profile and worse quality of life in the PD group. Two years after implant, 71% were no longer clinically catastrophizing and 58% were no longer clinically depressed. Notably, more than half of the PD patients on antidepressants discontinued or decreased their medication. Health-related quality of life was 82% higher in the PD group at 24 months, reaching levels similar to the ND group. Psychological distress did not impact outcomes after SCS therapy; composite multi-responder rates were similar in the two groups throughout the follow-up period. Patient reported pain relief (58% PD vs 61% ND) was equivalent in each group. In both groups, 81% were satisfied or very satisfied with the pain relief provided. Conclusions Our results showed that B-SCS appears to be as effective in a chronic pain population with high psychological distress as in those without distress. This may be due to the unique mechanism of action with the stimulation design involving the emotional-affective medial pain pathway in the brain.
... Importantly, in addition to somatosensory modulation, multiple neuroimaging and direct neuronal recording studies have revealed that B-SCS modulates the medial spinothalamocortical pathways, having a greater effect than tonic SCS on targets of the brain that are associated with the affective/ attentional or emotional aspects of pain processing (12,(17)(18)(19)(20). The full clinical implications of these differences have not been established, although B-SCS has shown to be more effective than tonic stimulation in several comparative studies (8,17,(21)(22)(23)(24)(25)(26). ...
Article
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Objective Burst spinal cord stimulation (B‐SCS) has been shown to reduce neuronal firing in the anterior cingulate cortex through selective modulation of the medial pain pathway tract. This pain pathway communicates the affective component of pain processing. The purpose of this study was to assess the effect of B‐SCS on psychosocial functioning and its influence on pain and quality of life. Materials and Methods Eligible patients with chronic, intractable pain of the trunk, and/or lower limbs were enrolled. After a successful trial period, subjects received a permanent implant and returned for follow‐up at 6‐ and 12‐months. Results In total, 269 patients were enrolled at 22 centers. Trial success rate was 90%. Significant improvements in pain, physical, mental, and emotional functioning were observed from baseline to the 6‐ and 12‐month follow‐up (p < 0.001). Overall, patients had improved quality of life, became more active, and the negative impact of pain on daily life was decreasing. At one year, 81% of subjects were satisfied or very satisfied with their therapy. Subjects showing significant improvements on mental health outcomes reported enhanced pain relief and quality of life scores compared with subjects with continued impaired mental health at follow‐up. At one year, 89% of subjects who were taking opioids at baseline decreased or stayed at the same level of opioid use; 19% stopped taking any opioids. No unanticipated adverse events have been reported. Conclusions One‐year outcomes after B‐SCS show improvements across all evaluated psychological measures with the largest impact observed on catastrophizing and depression (the affective component of pain processing). These pain‐related beliefs and behaviors, and not pain intensity, have been shown to put patients at greatest risk of a poor prognosis and quality of life.
... Their relapse could potentially be a result of the use of higher-frequency burst stimulation (10 Hz) compared to other participants (6 Hz burst). Previous studies have shown that burst compared to tonic stimulation is a substantially more powerful cortex activator [53] and has beneficial effects when applied to the auditory cortex for tinnitus [62], somatosensory cortex for pain [63] and anterior cingulate for AUD [49], OCD [64] and tinnitus [65], as well as on the spinal cord [66,67] and peripheral nerve [68] for pain. Based on case reports, it is suggested that theta frequencies between 4 and 7 Hz may be optimal for the anterior cingulate cortex [49,64,65]. ...
Article
Abnormal neural activity, particularly in the rostrodorsal anterior cingulate cortex (rdACC), appears to be responsible for intense alcohol craving. Neuromodulation of the rdACC using cortical implants may be an option for individuals with treatment-resistant alcohol dependence. This study assessed the effectiveness and feasibility of suppressing alcohol craving using cortical implants of the rdACC using a controlled one-group pre- and post-test study design. Eight intractable alcohol-dependent participants (four males and four females) were implanted with two Lamitrode 44 electrodes over the rdACC bilaterally connected to an internal pulse generator (IPG). The primary endpoint, self-reported alcohol craving reduced by 60.7% (p = 0.004) post- compared to pre-stimulation. Adverse events occurred in four out of the eight participants. Electrophysiology findings showed that among responders, there was a post-stimulation decrease (p = 0.026) in current density at the rdACC for beta 1 band (13–18 Hz). Results suggest that rdACC stimulation using implanted electrodes may potentially be a feasible method for supressing alcohol craving in individuals with severe alcohol use disorder. However, to further establish safety and efficacy, larger controlled clinical trials are needed.
Article
Background The field of otology is increasingly at the forefront of innovation in science and medicine. The inner ear, one of the most challenging systems to study, has been rendered much more open to inquiry by recent developments in research methodology. Promising advances of potential clinical impact have occurred in recent years in biological fields such as auditory genetics, ototoxic chemoprevention and organ of Corti regeneration. The interface of the ear with digital technology to remediate hearing loss, or as a consumer device within an intelligent ecosystem of connected devices, is receiving enormous creative energy. Automation and artificial intelligence can enhance otological medical and surgical practice. Otology is poised to enter a new renaissance period, in which many previously untreatable ear diseases will yield to newly introduced therapies. Objective This paper speculates on the direction otology will take in the coming decades. Conclusion Making predictions about the future of otology is a risky endeavour. If the predictions are found wanting, it will likely be because of unforeseen revolutionary methods.
Article
Tinnitus, the auditory phantom percept, is a well-known heterogenous disorder with multiple subtypes. Researchers and clinicians have tried to classify these subtypes according to clinical profiles, aetiologies, and response to treatment with little success. The occurrence of overlapping tinnitus subtypes suggests that the disorder exists along a continuum of severity, with no clear distinct boundaries. In this perspective, we propose a neuro-mechanical framework, viewing tinnitus as a dimensional disorder which is a complex interplay of its behavioural, biological and neurophysiological phenotypes. Moreover, we explore the potential of these dimensions as interacting networks without a common existing cause, giving rise to tinnitus. Considering tinnitus as partially overlapping, dynamically changing, interacting networks, each representing a different aspect of the unified tinnitus percept, suggests that the interaction of these networks determines the phenomenology of the tinnitus, ultimately leading to a dimensional spectrum, rather than a categorical subtyping. A combination of a robust theoretical framework and strong empirical evidence can advance our understanding of the functional mechanisms underlying tinnitus and ultimately, improve treatment strategies.
Article
Tinnitus is a phantom sensation of sound in the absence of external stimulation. Since the mechanism of tinnitus is not clearly discovered, no currently available treatments are ideal. There have been many published studies which report that electrical stimulation has a suppressive effect on tinnitus. Although there is no consensus stimulation method and regimen, electrical stimulation has emerged as an interesting and promising modality for tinnitus relief. In this review, authors collected and analyzed articles on electrical stimulation and outlined various methods of noninvasive and invasive stimulation.
Chapter
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1. The most frequent cause of tinnitus is hearing loss. 2. The auditory deprivation can lead to pathological theta–gamma coupling linked to a decrease of alpha oscillations also known as thalamocortical dysrhythmia. 3. Auditory deprivation also leads to auditory tract and auditory cortex tonotopic reorganization via activation of neural plasticity. 4. Presenting the missing information can reverse cortical reorganization. 5. Cortical stimulation can also reorganize tonotopic organization. 6. Auditory cortex stimulation can decrease tinnitus. 7. Auditory cortex stimulation interferes with ongoing oscillatory activity. 8. One in three patients responds to tonic stimulation and one in three to burst resulting in two out of three patients responding to auditory cortex stimulation. 9. Average improvement for auditory cortex stimulation is 50%. 10. Individuals with pure-tone tinnitus respond best to tonic stimulation of the cortex. 11. Individuals with noise-like tinnitus respond best to burst stimulation. 12. Tinnitus duration gender, or age is not predictive for successful stimulation.
Chapter
1. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive method for applying electromagnetic fields to the brain.
Article
Subjective chronic tinnitus consists of a more or less continuous perception of sound in the absence of a corresponding acoustic source, which can lead to various psychological problems like depression, anxiety, attentional deficits, and sleep disturbances. The prevalence is 10 to 15% of the general population. Various therapy and management options have been proposed, but outcomes vary and no generally accepted cure exists. In this review, the coherence of the most frequently used etiological models shall be evaluated and the efficacy of several treatment options will be discussed. With respect to tinnitus treatments, we focus on controlled studies and meta-analyses. Although there are some therapies that outweigh placebo effects such as cognitive behavioral therapy, neurofeedback, or neuromodulation techniques, they mainly target secondary symptoms and not the tinnitus tone itself. Furthermore, positive treatment effects only seem to last for a limited period of time. We conclude that long lasting combination therapies such as neurofeedback of auditory cortex inhibitory EEG signatures, cognitive therapy, and sound-tactile stimulation may provide more efficient outcomes if they target the intensity of the tinnitus tone itself and not only secondary psychological symptoms.
Article
Tinnitus is one of the most common otological symptoms and can be defined as the conscious perception of sound lasting more than 5 minutes in the absence of an external auditory stimulus. Based on the review of articles, a comparative analysis of modern methods of diagnosis and treatment of tinnitus was carried out in order to substantiate the most effective and promising algorithms for providing care to patients. Diagnosis of tinnitus includes taking anamnesis, assessing the severity of tinnitus using questionnaires, otoscopy, hearing examination, and performing additional tests. In case of secondary murmur, etiotropic therapy should be started as soon as possible to prevent hearing loss and other complications. For primary noise, the most effective treatments are cognitive-behavioral therapy, tinnitus maskers and sound therapy, transcutaneous electrical stimulation, and biofeedback. Magnetic stimulation, invasive neuromodulation, drug therapy have a lower level of effectiveness and evidence base.
Article
Neuromodulation, via stimulation of a variety of peripheral and central structures, is used to suppress tinnitus. However, investigative limitations in humans due to ethical reasons have made it difficult to decipher the mechanisms underlying treatment-induced tinnitus relief, so a number of animal models have arisen to address these unknowns. This chapter reviews animal models of cochlear and brain stimulation and assesses their modulatory effects on behavioral evidence of tinnitus and its related neural correlates. When a structure is stimulated, localized modulation, often presenting as downregulation of spontaneous neuronal spike firing rate, bursting and neurosynchrony, occurs within the brain area. Through anatomical projections and transmitter pathways, the interventions activate both auditory- and non-auditory structures by taking bottom-up ascending and top-down descending modes to influence their target brain structures. Furthermore, it is the brain oscillations that cochlear or brain stimulation evoke and connect the prefrontal cortex, striatal systems, and other limbic structures to refresh neural networks and relieve auditory, attentive, conscious, as well as emotional reactive aspects of tinnitus. This oscillatory neural network connectivity is achieved via the thalamocorticothalamic circuitry including the lemniscal and non-lemniscal auditory brain structures. Beyond existing technologies, the review also reveals opportunities for developing advanced animal models using new modalities to achieve precision neuromodulation and tinnitus abatement, such as optogenetic cochlear and/or brain stimulation.
Chapter
The pathophysiological mechanisms that underlie the generation and maintenance of tinnitus are being unraveled progressively. Based on this knowledge, a large variety of different neuromodulatory interventions have been developed and are still being designed, adapting to the progressive mechanistic insights in the pathophysiology of tinnitus. rTMS targeting the temporal, temporoparietal, and the frontal cortex has been the mainstay of non-invasive neuromodulation. Yet, the evidence is still unclear, and therefore systematic meta-analyses are needed for drawing conclusions on the effectiveness of rTMS in chronic tinnitus. Different forms of transcranial electrical stimulation (tDCS, tACS, tRNS), applied over the frontal and temporal cortex, have been investigated in tinnitus patients, also without robust evidence for universal efficacy. Cortex and deep brain stimulation with implanted electrodes have shown benefit, yet there is insufficient data to support their routine clinical use. Recently, bimodal stimulation approaches have revealed promising results and it appears that targeting different sensory modalities in temporally combined manners may be more promising than single target approaches.
Article
Tinnitus is a phantom auditory perception coded in the brain that can be bothersome or debilitating for 10-15% of the population. Currently, there is no clinically recommended drug or device treatment for this major health condition. Animal research has revealed that sound paired with electrical somatosensory stimulation can drive extensive plasticity within the brain for tinnitus treatment. To investigate this bimodal neuromodulation approach in humans, we evaluated a noninvasive device that delivers sound to the ears and electrical stimulation to the tongue in a randomized, double-blinded, exploratory study that enrolled 326 adult subjects with chronic subjective tinnitus. Participants were randomized into three parallel arms with different stimulation settings. Clinical outcomes were evaluated over a 12-week treatment period and a 12-month post-treatment phase. For the primary endpoints, participants achieved a statistically significant reduction in tinnitus symptom severity at the end of treatment based on two commonly used outcome measures, Tinnitus Handicap Inventory (Cohen’s d effect size: 0.87 to 0.92 across arms; p<0.001) and Tinnitus Functional Index (0.77 to 0.87; p<0.001). Therapeutic improvements continued for 12 months post-treatment for specific bimodal stimulation settings. Long-term benefits lasting 12 months have not previously been demonstrated in a large cohort for a tinnitus intervention. The treatment also achieved high compliance and satisfaction rates with no treatment-related serious adverse events. These positive therapeutic and long-term results motivate further clinical trials towards establishing bimodal neuromodulation as the first clinically recommended device treatment for tinnitus.
Chapter
Available treatments for the management of tinnitus are diverse. These include counseling and cognitive–behavioral therapies; different forms of sound therapies; methods that attempt to increase input to the auditory system, such as hearing aids and cochlear implants (for use in patients whose tinnitus is caused by deprivation of signals to the auditory nervous system); pharmacological treatment; neurobiofeedback; and various forms of electrical stimulation of brain structures, either through implanted electrodes or by inducing electrical current in the brain with transcranial magnetic stimulation. The existence of many different treatment approaches derives from the fact that there exist different subgroups of tinnitus that differ in their pathophysiology and their response to treatment. In clinical practice it is frequently difficult to choose the optimal treatment approach for an individual patient. The treatment approaches presented in this chapter (pharmacological, magnetic, or electrical brain stimulation) are all at early stages of development. The further development of these new treatment options will depend on the extent to which we understand the pathophysiology of the different forms of tinnitus.
Article
Background:Visceral pain can be disabling for patients and challenging to treat in the clinic. Spinal cord stimulation is a NICE approved treatment for chronic neuropathic pain, presenting potential advantages over conventional therapies for managing chronic visceral pain. Results: A retrospective study revealed that a specific type of spinal cord stimulation, BurstDR TM (Abbott, TX, USA), was effective at improving pain and quality of life in patients with chronic visceral pain. Baseline pain scores significantly correlated with change at follow-up, suggesting it may be possible to identify potential responders from the outset. BurstDR was safe: rates of revision, explantation and complications were low. Conclusion: Clinical trials exploring the long-term effects of BurstDR including a control arm are needed. Findings could have the potential to inform best practice and improve outcomes for individuals with chronic visceral pain.
Article
Background: Invasive neuromodulation of the cortical surface for various chronic pain syndromes has been performed for >20 years. The significance of motor cortex stimulation (MCS) in chronic trigeminal neuropathic pain (TNP) syndromes remains unclear. Different techniques are performed worldwide in regard to operative procedure, stimulation parameters, test trials, and implanted materials. Objective: To present the clinical experiences of a single center with MCS, surgical approach, complications, and follow-up as a prospective, noncontrolled clinical trial. Methods: The implantation of epidural leads over the motor cortex was performed via a burr hole technique with neuronavigation and intraoperative neurostimulation. Special focus was placed on a standardized test trial with an external stimulation device and the implementation of a double-blinded or placebo test phase to identify false-positive responders. Results: A total of 36 patients with TNP were operated on, and MCS was performed. In 26 of the 36 patients (72%), a significant pain reduction from a mean of 8.11 to 4.58 (on the visual analog scale) during the test trial was achieved (P < .05). Six patients were identified as false-positive responders (17%). At the last available follow-up of 26 patients (mean, 5.6 years), active MCS led to a significant pain reduction compared with the preoperative pain ratings (mean visual analog scale score, 5.01; P < .05). Conclusion: MCS is an additional therapeutic option for patients with refractory chronic TNP, and significant long-term pain suppression can be achieved. Placebo or double-blinded testing is mandatory. Abbreviations: MCS, motor cortex stimulationNRS, numeric pain rating scaleTNP, trigeminal neuropathic or deafferentation painVAS, visual analog scale.
Article
OBJECTIVE The objective of this open-label, nonrandomized trial was to evaluate the efficacy and safety of bilateral caudate nucleus deep brain stimulation (DBS) for treatment-resistant tinnitus. METHODS Six participants underwent DBS electrode implantation. One participant was removed from the study for suicidality unrelated to brain stimulation. Participants underwent a stimulation optimization period that ranged from 5 to 13 months, during which the most promising stimulation parameters for tinnitus reduction for each individual were determined. These individual optimal stimulation parameters were then used during 24 weeks of continuous caudate stimulation to reach the endpoint. The primary outcome for efficacy was the Tinnitus Functional Index (TFI), and executive function (EF) safety was a composite z-score from multiple neuropsychological tests (EF score). The secondary outcome for efficacy was the Tinnitus Handicap Inventory (THI); for neuropsychiatric safety it was the Frontal Systems Behavior Scale (FrSBe), and for hearing safety it was pure tone audiometry at 0.5, 1, 2, 3, 4, and 6 kHz and word recognition score (WRS). Other monitored outcomes included surgery- and device-related adverse events (AEs). Five participants provided full analyzable data sets. Primary and secondary outcomes were based on differences in measurements between baseline and endpoint. RESULTS The treatment effect size of caudate DBS for tinnitus was assessed by TFI [mean (SE), 23.3 (12.4)] and THI [30.8 (10.4)] scores, both of which were statistically significant (Wilcoxon signed-rank test, 1-tailed; alpha = 0.05). Based on clinically significant treatment response categorical analysis, there were 3 responders determined by TFI (≥ 13-point decrease) and 4 by THI (≥ 20-point decrease) scores. Safety outcomes according to EF score, FrSBe, audiometric thresholds, and WRS showed no significant change with continuous caudate stimulation. Surgery-related and device-related AEs were expected, transient, and reversible. There was only one serious AE, a suicide attempt unrelated to caudate neuromodulation in a participant in whom stimulation was in the off mode for 2 months prior to the event. CONCLUSIONS Bilateral caudate nucleus neuromodulation by DBS for severe, refractory tinnitus in this phase I trial showed very encouraging results. Primary and secondary outcomes revealed a highly variable treatment effect size and 60%–80% treatment response rate for clinically significant benefit, and no safety concerns. The design of a phase II trial may benefit from targeting refinement for final DBS lead placement to decrease the duration of the stimulation optimization period and to increase treatment effect size uniformity. Clinical trial registration no.: NCT01988688 (clinicaltrials.gov).
Article
Background: Obsessive-compulsive disorder (OCD) is a brain disorder with a lifetime prevalence of 2.3%, causing severe functional impairment as a result of anxiety and distress, persistent and repetitive, unwanted, intrusive thoughts (obsessions), and repetitive ritualized behavior (compulsions). Approximately 40%-60% of patients with OCD fail to satisfactorily respond to standard treatments. Intractable OCD has been treated by anterior capsulotomy and cingulotomy, but more recently, neurostimulation approaches have become more popular because of their reversibility. Objective: Implants for OCD are commonly being used, targeting the anterior limb of the internal capsula or the nucleus accumbens, but an implant on the anterior cingulate cortex has never been reported. Methods: We describe a patient who was primarily treated for alcohol addiction, first with transcranial magnetic stimulation, then by implantation of 2 electrodes overlying the rostrodorsal part of the anterior cingulate cortex bilaterally. Results: Her alcohol addiction developed as she was relief drinking to self-treat her OCD, anxiety, and depression. After the surgical implant, she underwent placebo stimulation followed by real stimulation of the dorsal anterior cingulate cortex, which dramatically improved her OCD symptoms (decrease of 65.5% on the Yale-Brown Obsessive Compulsive Drinking Scale) as well as her alcohol craving (decrease of 87.5%) after 36 weeks of treatment. Although there were improvements in all the scores, there was only a modest reduction in the patient's weekly alcohol consumption (from 50 units to 32 units). Conclusions: Based on these preliminary positive results we propose to further study the possible beneficial effect of anterior cingulate cortex stimulation for intractable OCD.
Chapter
The aim of this chapter is to review the current significance of motor cortex stimulation (MCS) for either chronic neuropathic pain or non-painful conditions. The epi- or subdural lead implantation over the central sulcus or precentral gyrus is performed in selected patients if conservative treatments, pharmacological therapies and multimodal settings are ineffective. Initial case series with post-stroke pain or trigeminal neuropathic pain were published in the early 1990s. To date more than 700 cases and about 75 prospective or retrospective clinical trials, patient samples or reviews are published. The exact mode of action is unknown but functional studies using magnetic resonance imaging (MRI) or single-photon emission computed tomography (SPECT) reveal a certain modulation of pain-related subcortical areas like the thalamus, cingulate gyrus, etc. via corticothalamic and other connections. The focus of this chapter is to highlight the clinical practical aspects of patient selection and performance of the procedure as an individual and therefore experimental treatment option. At the moment, all implanted materials are used off-label because there is no approval for this specific indication. The current evidence of these invasive procedures for different diagnoses is presented.
Chapter
This chapter discusses several system aspects for the design of neural stimulator circuits and provides a framework to compare such designs in general. Throughout the chapter, a comparison is made between the neural stimulator designs that are to be discussed in more detail in Chaps. 6 and 7. Both designs have been created with a different application in mind and this chapter discusses the consequences.
Chapter
This chapter discusses the design of an arbitrary waveform, charge balanced biphasic stimulator. The philosophy behind the system is to give the user full flexibility in the choice for the stimulation waveform, while the safety is ensured by implementing a charge balance mechanism. As discussed in Chap. 5 the stimulation waveform can benefit from the complex dynamics of the axon membrane in order to induce recruitment in a more efficient way. Furthermore, burst stimulation can be considered to be a special stimulation waveform as well, which has also shown to have advantages.
Article
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Neuromodulation is a clinical tool used for treating chronic neuropathic pain by transmitting controlled physical energy to the pre‐identified neural targets in the central nervous system. Its drug‐free, nonaddictive, and improved targeting characteristics have attracted increasing attention among neuroscience research and clinical practices. This article provides a brief overview of the neuropathic pain and pharmacological routines for treatment, summarizes both the invasive and noninvasive neuromodulation modalities for pain management, and highlights an emerging brain stimulation technology, transcranial focused ultrasound (tFUS), with a focus on ultrasound transducer devices and the achieved neuromodulation effects and applications on pain management. Practical considerations of spatial guidance for tFUS are discussed for clinical applications. The safety of transcranial ultrasound neuromodulation and its future prospectives on pain management are also discussed.
Article
Introduction: Burst stimulation, as described by DeRidder, is a novel waveform made up of closely spaced, high-frequency electrical impulses delivered in packets, which are followed by a quiescent period or interburst interval. Electrically generated burst waveforms were initially designed to treat neural pathology in the auditory cortex and were later applied to the spinal cord through spinal cord stimulation (SCS) devices to treat chronic pain states. When Burst stimulation is applied to the spinal cord, the impulses travel to the thalamus and then diverge, targeting both the somatosensory cortex and the limbic system where they treat both the sensory, affective and attentional components of neuropathic pain. Areas Covered: Literature examining clinical and basic research findings with the application of Burst stimulation to pathologically active central neural tissue was found using bibliographic databases including PubMed, Medline, Cochrane, Embase and Google Scholar. Expert Commentary: Burst stimulation offers a salvage strategy for failed tonic spinal cord stimulation (tSCS), thus improving both quality of life and cost-effectiveness of SCS by reducing explant rates. The goal of this therapy is to use more than one waveform in the same device so that lost efficacy from tSCS can be salvaged.
Article
Background: The anterior cingulate cortex (ACC) has been implicated in both cognitive and emotional processing, with cognitive information proposed to be processed through the dorsal/caudal ACC and emotional information through the rostral/ventral ACC. Objective: The objective of this study is to investigate the role of the dorsal anterior cingulate cortex (dACC) in cognitive and emotional processing using a cognitive and emotional counting Stroop task in two patients in whom abnormalities in the dACC were identified and treated. Methods: Two patients performed the cognitive and emotional counting Stroop task before and after treatment to examine whether the dACC has a specific or more general processing function. Results: We observed an overall improvement in the emotional, cognitive, and neutral trials of the counting Stroop task after the intervention, indicating that the dACC is not a subregion of the ACC that only contributes to a specific domain. Conclusion: This study reveals that the dACC is not just a subregion of the ACC that contributes to a specific cognitive function, but is rather part of a salience network that influences general brain functioning, influencing cognitive as well as emotional processing.
Chapter
The future of psychiatric neurosurgery can be viewed from two separate perspectives: the immediate future and the distant future. Both show promise, but the treatment strategy for mental diseases and the technology utilized during these separate periods will likely differ dramatically. It can be expected that the initial advancements will be built upon progress of neuroimaging and stereotactic targeting while surgical technology becomes adapted to patient-specific symptomatology and structural/functional imaging parameters. This individualized approach has already begun to show significant promise when applied to deep brain stimulation for treatment-resistant depression and obsessive-compulsive disorder. If effectiveness of these strategies is confirmed by well designed, double-blind, placebo-controlled clinical studies, further technological advances will continue into the distant future, and will likely involve precise neuromodulation at the cellular level, perhaps using wireless technology with or without closed-loop design. This approach, being theoretically less invasive and carrying less risk, may ultimately propel psychiatric neurosurgery to the forefront in the treatment algorithm of mental illness. Despite prominent development of non-invasive therapeutic options, such as stereotactic radiosurgery or transcranial magnetic resonance-guided focused ultrasound, chances are there will still be a need in surgical management of patients with most intractable psychiatric conditions.
Chapter
Since 2010, we have witnessed a great increase in the clinical availability of the expressions of waveform research. Though the benefits of traditional, tonic stimulation are well proven, significant interest is arising in alternative waveforms and frequencies such as burst, high-frequency, and high-energy/high-density. Additional attention has focused on the impact of energy delivery, specifically the concepts around charge delivery and associated neurophysiologic changes in the spinal cord. The aim of modulating unconventional neural targets such as the dorsal root ganglion will likely uncover mechanisms that could lead to improved responses to pain. This chapter seeks to familiarize the reader with new waveform modalities, their proposed mechanism of action, and the relevant literature.
Article
Purpose: To review contributions of the American Otological Society (AOS) over the most recent quarter century (1993-2018) and to comment on possible future evolution of the field during the quarter century to come. Methods: Retrospective review of selected topics from the AOS transactions, distinguished lectureships over the past 25 years, and selective reflection by the authors. Speculation on potential advances of the next quarter century derived from emerging topics in the current literature and foreseeable trends in science and technology are also proffered for consideration (and possible future ridicule). Results: Integration of multiple disciplines including bioengineering, medical imaging, genetics, molecular biology, physics, and evidence based medicine have substantially benefitted the practice of otology over the past quarter century. The impact of the contributions of members of the AOS in these developments cannot be over estimated. Conclusions: Further scientific advancement will certainly accelerate change in the practice of otologic surgery and medicine over the coming decade in ways that will be marvelous to behold.
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Background: The field of neuromodulation is continually evolving, with the past decade showing significant advancement in the therapeutic efficacy of neuromodulation procedures. The continued evolution of neuromodulation technology brings with it the promise of addressing the needs of both patients and physicians, as current technology improves and clinical applications expand. Design: This review highlights the current state of the art of neuromodulation for treating chronic pain, describes key areas of development including stimulation patterns and neural targets, expanding indications and applications, feedback-controlled systems, noninvasive approaches, and biomarkers for neuromodulation and technology miniaturization. Results and conclusions: The field of neuromodulation is undergoing a renaissance of technology development with potential for profoundly improving the care of chronic pain patients. New and emerging targets like the dorsal root ganglion, as well as high-frequency and patterned stimulation methodologies such as burst stimulation, are paving the way for better clinical outcomes. As we look forward to the future, neural sensing, novel target-specific stimulation patterns, and approaches combining neuromodulation therapies are likely to significantly impact how neuromodulation is used. Moreover, select biomarkers may influence and guide the use of neuromodulation and help objectively demonstrate efficacy and outcomes.
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Introduction Dorsal root ganglion (DRG) stimulation demonstrated superiority over traditional spinal cord stimulation with better pain relief and greater improvement of quality of life. However, leads specifically designed for DRG stimulation are difficult to implant in patients who previously underwent spinal surgery and show epidural scarring at the desired site of implantation because of the reduced stiffness of the lead. Nevertheless, recurrent leg or arm pain after spinal surgery usually manifests as a single level radiculopathy, which should theoretically be amenable to DRG stimulation. Materials and Methods We present the percutaneous transforaminal placement of cylindrical leads through a lateral endoscopic approach for DRG stimulation in burst mode. Results We could successfully show that percutaneous transforaminal lead placement is feasible in three illustrative cases. Conclusion This technical note combines two innovations, one linked to the other. The first innovation involves a novel endoscopic lateral transforaminal approach to insert a cylindrical lead to the DRG. Because this electrode is compatible with burst stimulation-enabled devices, a second innovation consists of the application of burst stimulation on the DRG.
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Tinnitus is hypothesized to be an auditory phantom phenomenon resulting from spontaneous neuronal activity somewhere along the auditory pathway. We performed fMRI of the entire auditory pathway, including the inferior colliculus (IC), the medial geniculate body (MGB) and the auditory cortex (AC), in 42 patients with tinnitus and 10 healthy volunteers to assess lateralization of fMRI activation. Subjects were scanned on a 3T MRI scanner. A T2*-weighted EPI silent gap sequence was used during the stimulation paradigm, which consisted of a blocked design of 12 epochs in which music presented binaurally through headphones, which was switched on and off for periods of 50 s. Using SPM2 software, single subject and group statistical parametric maps were calculated. Lateralization of activation was assessed qualitatively and quantitatively. Tinnitus was lateralized in 35 patients (83%, 13 right-sided and 22 left-sided). Significant signal change (P(corrected) < 0.05) was found bilaterally in the primary and secondary AC, the IC and the MGB. Signal change was symmetrical in patients with bilateral tinnitus. In patients with lateralized tinnitus, fMRI activation was lateralized towards the side of perceived tinnitus in the primary AC and IC in patients with right-sided tinnitus, and in the MGB in patients with left-sided tinnitus. In healthy volunteers, activation in the primary AC was left-lateralized. Our paradigm adequately visualized the auditory pathways in tinnitus patients. In lateralized tinnitus fMRI activation was also lateralized, supporting the hypothesis that tinnitus is an auditory phantom phenomenon.
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Phantom auditory perception--tinnitus--is a symptom of many pathologies. Although there are a number of theories postulating certain mechanisms of its generation, none have been proven yet. This paper analyses the phenomenon of tinnitus from the point of view of general neurophysiology. Existing theories and their extrapolation are presented, together with some new potential mechanisms of tinnitus generation, encompassing the involvement of calcium and calcium channels in cochlear function, with implications for malfunction and aging of the auditory and vestibular systems. It is hypothesized that most tinnitus results from the perception of abnormal activity, defined as activity which cannot be induced by any combination of external sounds. Moreover, it is hypothesized that signal recognition and classification circuits, working on holographic or neuronal network-like representation, are involved in the perception of tinnitus and are subject to plastic modification. Furthermore, it is proposed that all levels of the nervous system, to varying degrees, are involved in tinnitus manifestation. These concepts are used to unravel the inexplicable, unique features of tinnitus and its masking. Some clinical implications of these theories are suggested.
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The sources of ascending input to the medial geniculate body (MGB) of the cat were studied using the retrograde transport of horseradish peroxidase (HRP). HRP injections were made iontophoretically through micropipettes which were also used to record physiological properties at the injection sites. This technique produced small injections which appeared to be restricted to single subnuclei. The tectothalamic projection of the auditory system was found to consist of at least four distinct and separate pathways. The ventral division of the MGB receives a topographical projection from the central nucleus of the inferior colliculus (ICC) which preserves tonotopicity and provides short latency, sharply frequency-tuned responses. The medial part of the ICC projects to the deep dorsal nucleus, which contains only units tuned to high frequencies. The major inputs to the caudodorsal nucleus (DC) stem from nucleus sagulum and the pericentral nucleus of the inferior colliculus (ICP). Units in DC and the ventrolateral nucleus, which also receive input from ICP, have very broad tuning properties and late, habituating responses. Injections of HRP into the medial division (MGM) produced labeled cells scattered throughout the external nucleus of the inferior colliculus and the ventral part of ICC. This widespread input is reflected in the wide range of auditory responses found in MGM. Auditory responses in the suprageniculate nucleus were poorly defined and many units did not respond to tonal stimuli; following HRP injections no filled cells were found in the inferior colliculus, but labeled cells were found in the deeper layers of the superior colliculus and in the interstitial nucleus of the brachium of the inferior colliculus. Together with recent findings on the auditory thalamocortical projection, these results provide evidence for multiple parallel auditory pathways through the thalamus.
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Although phantom-limb pain is a frequent consequence of the amputation of an extremity, little is known about its origin. On the basis of the demonstration of substantial plasticity of the somatosensory cortex after amputation or somatosensory deafferentation in adult monkeys, it has been suggested that cortical reorganization could account for some non-painful phantom-limb phenomena in amputees and that cortical reorganization has an adaptive (that is, pain-preventing) function. Theoretical and empirical work on chronic back pain has revealed a positive relationship between the amount of cortical alteration and the magnitude of pain, so we predicted that cortical reorganization and phantom-limb pain should be positively related. Using non-invasive neuromagnetic imaging techniques to determine cortical reorganization in humans, we report a very strong direct relationship (r = 0.93) between the amount of cortical reorganization and the magnitude of phantom limb pain (but not non-painful phantom phenomena) experienced after arm amputation. These data indicate that phantom-limb pain is related to, and may be a consequence of, plastic changes in primary somatosensory cortex.
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Positive symptoms arise after lesions of the nervous system. They include neurogenic pain, tinnitus, abnormal movements, epilepsy and certain neuropsychiatric disorders. Stereotactic medial thalamotomies were performed on 104 patients with chronic therapy-resistant positive symptoms. Peroperative recordings of 2012 single units revealed an overwhelming unresponsiveness (99%) to sensory stimuli or motor activation. Among these unresponsive cells, 45.1% presented a rhythmic or random bursting activity. Rhythmic bursting activities had an average interburst interval of 263±46 ms corresponding to a frequency of 3.8±0.7 Hz. Frequency variations among the different symptoms were not statistically different. Intraburst characteristics such as the highest frequency encountered in the burst (480±80 Hz) or the mean frequency of the burst (206±44 Hz) were also similar in all patients. All bursts, rhythmic or random, fulfilled the extracellular criteria of low-threshold calcium spike (LTS) bursts. After medial thalamotomy and depending on the symptom, 43–67% of the patients reached a 50–100% relief, with sparing of all neurological functions. On the basis of these electrophysiological and clinical results, we propose a unified concept for all positive symptoms centred on a self-perpetuating thalamic cell membrane hyperpolarization, similar to the one seen in slow-wave sleep.
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Magnetic source imaging was used to determine whether tonotopy in auditory cortex of individuals with tinnitus diverges from normative functional organization. Ten tinnitus subjects and 15 healthy controls were exposed to four sets of tones while magnetoencephalographic recordings were obtained from the two cortical hemispheres in sequence. A marked shift of the cortical representation of the tinnitus frequency into an area adjacent to the expected tonotopic location was observed. The Euclidean distance of the tinnitus frequency from the trajectory of the tonotopic map was 5.3 mm (SD = 3.1) compared with a distance of 2.5 mm (SD = 1.3) of a corresponding frequency in the healthy controls (t = 3.13, P < 0.01). In addition, a strong positive correlation was found between the subjective strength of the tinnitus and the amount of cortical reorganization (r = 0.82, P < 0.01). These results demonstrate that tinnitus is related to plastic alterations in auditory cortex. Similarities between these data and the previous demonstrations that phantom limb pain is highly correlated with cortical reorganization suggest that tinnitus may be an auditory phantom phenomenon.
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Thalamocortical and perigeniculate (PGN) neurons can generate action potentials either as Ca2+ spike-mediated high-frequency bursts or as tonic trains. Using dual intracellular recordings in vitro in monosynaptically connected pairs of PGN and dorsal lateral geniculate nucleus (LGNd) neurons, we found that the functional effect of synaptic transmission between these cell types was strongly influenced by the membrane potential and hence the firing mode of both the pre- and postsynaptic neurons. Activation of single action potentials or low-frequency spike trains in PGN or thalamocortical neurons resulted in the generation of PSPs that were 0.5-2.0 mV in amplitude. In contrast, the generation of Ca2+ spike-mediated bursts of action potentials in the presynaptic cell increased these PSPs to an average of 4.4 mV for the IPSP and 3.0 mV for the EPSP barrage, because of temporal summation and/or facilitation. If the postsynaptic neuron was at a resting membrane potential (e.g., -65 mV), these PSP barrages could result in the activation of a low-threshold Ca2+ spike and burst of action potentials. These results demonstrate that the burst firing mode of action potential generation is a particularly effective means by which perigeniculate and thalamocortical neurons may influence one another. We propose that the activation of burst discharges in these cell types is essential for the generation of some forms of synchronized rhythmic oscillations of sleep and of epileptic seizures.
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The symptoms and signs of severe tinnitus and chronic pain have many similarities and similar hypotheses have been presented regarding how the symptoms are generated. Pain and tinnitus have many different forms. The severity of the symptoms of both varies within wide limits, and it is not likely that all forms have the same pathology. Some individuals with severe tinnitus perceive sounds to be unpleasant or painful. This may be similar to what is known as allodynia, which is a painful sensation of normally innocuous stimulation of the skin. Many individuals with chronic pain experience a worsening of their pain from repeated stimulation (the "wind-up" phenomenon). This is similar to the increasingly unpleasant feeling from sounds that are repeated that many individuals with severe tinnitus experience. There are also similarities in the hypotheses about the generation of pain and tinnitus. Although less severe tinnitus may be generated in the ear, it is believed that severe tinnitus in many cases is caused by changes in the nervous system that occur as a result of neural plasticity. Acute pain caused by tissue injury is generated at the site of injury but chronic pain is often generated in the central nervous system, yet another similarity between chronic pain and severe tinnitus. The changes in the nervous system consist of altered synaptic efficacy including opening of dormant synapses. For pain, this is believed to occur in the wide dynamic range neurons of the spinal cord and brain stem. Less is known about the anatomic location of the changes that cause severe tinnitus but there are indications that it may be the inferior colliculus. It is also possible that other auditory systems than the classical ascending pathways may be involved in severe tinnitus.
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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.
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Burst firing is commonly observed in many sensory systems and is proposed to transmit information reliably. Although a number of biophysical burst mechanisms have been identified, the relationship between burst dynamics and information transfer is uncertain. Electrosensory pyramidal cells have a well defined backpropagation-dependent burst mechanism. We used in vivo, in vitro, and modeling approaches to investigate pyramidal cell responses to mimics of behaviorally relevant sensory input. We found that within a given spike train, bursts are biased toward low-frequency events while isolated spikes simultaneously code for the entire frequency range. We also demonstrated that burst dynamics are essential for optimal feature detection but are not required for stimulus estimation. We conclude that burst and spike dynamics can segregate a single spike train into two parallel and complementary streams of information transfer.
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It is well known that some neurons tend to fire packets of action potentials followed by periods of quiescence (bursts) while others within the same stage of sensory processing fire in a tonic manner. However, the respective computational advantages of bursting and tonic neurons for encoding time varying signals largely remain a mystery. Weakly electric fish use cutaneous electroreceptors to convey information about sensory stimuli and it has been shown that some electroreceptors exhibit bursting dynamics while others do not. In this study, we compare the neural coding capabilities of tonically firing and bursting electroreceptor model neurons using information theoretic measures. We find that both bursting and tonically firing model neurons efficiently transmit information about the stimulus. However, the decoding mechanisms that must be used for each differ greatly: a non-linear decoder would be required to extract all the available information transmitted by the bursting model neuron whereas a linear one might suffice for the tonically firing model neuron. Further investigations using stimulus reconstruction techniques reveal that, unlike the tonically firing model neuron, the bursting model neuron does not encode the detailed time course of the stimulus. A novel measure of feature detection reveals that the bursting neuron signals certain stimulus features. Finally, we show that feature extraction and stimulus estimation are mutually exclusive computations occurring in bursting and tonically firing model neurons, respectively. Our results therefore suggest that stimulus estimation and feature extraction might be parallel computations in certain sensory systems rather than being sequential as has been previously proposed.
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Neurons in the lateral geniculate nucleus (LGN) of the thalamus produce spikes that can be classified as burst spikes and tonic spikes. Although burst spikes are generally associated with states of sleep and drowsiness, bursts may also play an important role in sensory processing. This study explores the stimulus properties that evoke burst and tonic spikes and examines the reliability of LGN neurons to produce visually driven bursts. Using reverse-correlation techniques, we show that the receptive fields of burst spikes are similar to, but significantly different from, the receptive fields of tonic spikes. Compared with tonic spikes, burst spikes (1) occur with a shorter latency between stimulus and response, (2) have a greater dependence on stimuli with transitions from suppressive to preferred states, and (3) prefer stimuli that provide increased drive to the receptive field center and even greater increased drive to the receptive field surround. These differences are not attributable to the long interspike interval that precedes burst spikes, because tonic spikes with similar preceding interspike intervals also differ from burst spikes in both the spatial and temporal domains. Finally, measures of reliability are significantly greater for burst spikes than for tonic spikes with similar preceding interspike intervals. These results demonstrate that thalamic bursts contribute to sensory processing and can reliably provide the cortex with information that is similar to, but distinct from, that of tonic spikes.
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Exposure to sound of sufficient duration and level causes permanent damage to the peripheral auditory system, which results in the reorganization of the cortical tonotopic map. The changes are such that neurons with pre-exposure tuning to frequencies in the hearing loss range now become tuned to frequencies near the near-normal lower boundary of the hearing loss range, which thus becomes over represented. However, cats exposed to a traumatizing noise and immediately thereafter placed for a few weeks in an enriched acoustic environment presented a much-restricted hearing loss compared with similarly exposed cats that were placed for the same time in a quiet environment. The enriched environment spectrally matched the expected hearing loss range and was approximately 40 dB above the level of the expected hearing loss. The hearing loss in the quiet environment-reared cats ranged from 6 to 32 kHz with the largest loss (on average, 40 dB) ranging from 24 to 32 kHz. In contrast, the hearing loss in the enriched-environment cats was restricted to 6-8 kHz at a level of, on average, 35 dB and with 16-32 kHz having normal thresholds. Despite the remaining hearing loss for the enriched-environment cats in the 6-8 kHz range, plastic tonotopic map changes in primary auditory cortex could no longer be demonstrated, suggesting that the enriched acoustic environment prevents this reorganization. This finding has implications for the treatment of hearing disorders, such as tinnitus, that have been linked to cortical tonotopic map reorganization.
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The clinical examination of patients with severe and chronic tinnitus must include associated psychological disturbances. The present paper describes traditional diagnostic methods of ENT practice as well as the Tinnitus Questionnaire (TQ) which has been evaluated in a number of studies. This instrument differentiates between emotional and cognitive distress, auditory perceptual difficulties and self-experienced intrusiveness produced by the tinnitus. The results of a German multicenter study are presented which show that the TQ can be used to demonstrate differences of tinnitus distress under different clinical conditions (e.g., ENT clinic vs psychosomatic clinic and in- vs outpatient care). The TQ can be employed for comparative studies in different tinnitus-related institutions and for the evaluation of the relative effects of different treatment approaches.
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Objectives/hypothesis: Low-frequency repetitive transcranial magnetic stimulation (rTMS) has been shown to alleviate tinnitus perception, presumably by inhibiting cortical activity associated with tinnitus. We conducted a pilot study to assess effectiveness of neuronavigated rTMS and its effects on attentional deficits and cortical asymmetry in four patients with chronic tinnitus using objective and subjective measures and employing an optimization technique refined in our laboratory. Study design: Randomized, placebo-controlled (sham stimulation) crossover study. Methods: Patients received 5 consecutive days of active, low-frequency rTMS or sham treatment (using a 45-degree coil-tilt method) before crossing over. Subjective tinnitus was assessed at baseline, after each treatment, and 4 weeks later. Positron emission tomography/computed tomography (PET/CT) scans were obtained at baseline and immediately after active treatment to examine change in cortical asymmetry. Attentional vigilance was assessed at baseline and after each treatment using a simple reaction time test. Results: All patients had a response to active (but not sham) rTMS, as indicated by their best tinnitus ratings; however, tinnitus returned in all patients by 4 weeks after active treatment. All patients had reduced cortical activity visualized on PET immediately after active rTMS. Mean reaction time improved (P < .05) after active but not sham rTMS. Conclusions: rTMS is a promising treatment modality that can transiently diminish tinnitus in some individuals, but further trials are needed to determine the optimal techniques required to achieve a lasting response. It is unclear whether the improved reaction times were caused by tinnitus reduction or a general effect of rTMS. PET/CT scans immediately after treatment suggest that improvement may be related to reduction of cortical asymmetry associated with tinnitus.
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Two tonotopically organized cortical fields, the primary (AI) and the rostral (R) fields, comprise the core of auditory cortex in the owl monkey. Injections of tritiated proline were made into each of these fields to determine their efferent projections using autoradiographic methods. Both AI and R project to the principal and magnocellular divisions of the medial geniculate body. In addition, R projects to the posterior part of the dorsal division of the medial geniculate. AI sends axons to the dorsomedial region and laminated portion of the central nucleus of the inferior colliculus. Labeling in the central nucleus following AI injections appears as a band of silver grains oriented parallel to isofrequency contours. Axons from R terminate in the dorsomedial region of the central nucleus of the inferior colliculus and in the pericentral and external nuclei of the inferior colliculus. In addition, the rostral field projects to a small area of the medial pulvinar just anterior to the brachium of the superior colliculus.
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1. In an anesthetized, paralyzed in vivo preparation, we recorded extracellular responses of 61 geniculate neurons (2 W, 25 X, 33 Y, and 1 mixed) to drifting sine-wave gratings of various spatial frequency, temporal frequency, and contrast. Our goal was to study the differential contributions to these visual responses of bursting caused by voltage dependent, low-threshold (LT) Ca2+ spikes and of purely tonic responses unrelated to LT spikes. Cells responding with LT spikes are said to be in the burst firing mode and those responding in a purely tonic fashion to be in the relay or tonic firing mode. We separated the total visual response into LT burst and tonic components by use of the empirical criteria set forth in our intracellular study described in the previous paper (Lu et al. 1992). A response component was considered to be an LT burst if its action potentials displayed interspike intervals < or = 4 ms and if the first spike in the burst episode occurred after a silent period of > or = 100 ms (or > or = 50 ms when the neuron responds to visual stimuli at temporal rates > or = 8 Hz). All other activity is considered to be part of the tonic response. 2. In addition to LT bursts, we recognized another type of burst response, the high-threshold (HT) burst. These also have clusters of action potentials with interspike intervals < or = 4 ms. However, HT bursts, unlike LT bursts, lack a preburst silent period. HT bursts are part of the tonic response component and merely reflect the gradual decrease in interspike intervals that occurs as the cell becomes more depolarized and thus more responsive. Thus interspike interval is a necessary but insufficient criterion to identify LT bursts. 3. Visually evoked LT bursts were recorded among W, X, and Y cells. When evoked, LT bursts occurred in phase with drifting sine-wave grating stimuli at a rate never exceeding one per stimulus cycle. In response to individual cycles of the visual stimulus, LT bursts could comprise the total response, a tonic component could comprise the total response, or an LT burst and tonic component could be mixed. When a stimulus evoked a mixture of LT bursts and tonic response components, LT bursts were always the first response. 4. Of the 61 cells tested with grating stimuli, 47 exhibited LT bursts and 14 did not. Those that did exhibited varying amounts of burstiness.(ABSTRACT TRUNCATED AT 400 WORDS)
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In order to produce choreic movements in monkeys (Macaca species), we have used the combination of unilateral kainic acid injections into the striatum and the systemic administration of L-DOPA. Two control monkeys received kainic acid injections alone and 7 were also given L-DOPA (150-300 mg/day) orally. No spontaneous involuntary movements were seen after kainic acid injection alone (over a period of 4-14 days). In the 7 monkeys that received L-DOPA 4-7 days after the kainic acid injection, in 5, whose striatal lesions were located in the rostral dorsolateral striatum, choreic movements appeared in the contralateral limbs following each dose of L-DOPA, whereas in 2 monkeys in which the lesion was large enough to occupy more than 60% of the rostral striatum, no choreic movements occurred. Preservation of some part of the striatum is therefore necessary for the generation of choreic movements. A considerable number of neurons in the rostral ventromedial putamen, which escaped the kainic acid lesion showed burst discharges when L-DOPA was administered. These were not seen in the caudate nucleus. The burst discharges recorded from some neurons were time-locked to the choreic movements. Since deafferentiation by dorsal root section had no effect, these burst discharges appeared to be generated in the unlesioned striatum during the choreic movements. Brains of 6 monkeys were analysed biochemically for gamma-aminobutyric acid concentration, choline acetyltransferase and tyrosine hydroxylase activity, and spiroperidol binding. Concentrations of gamma-aminobutyric acid, choline acetyltransferase activity and spiroperidol binding in the basal ganglia did not correlate with the generation of choreic movements. A finding which appeared to have a clear correlation was an increase in excess of 50% in tyrosine hydroxylase activity in the rostral ventromedial striatum on the lesioned side which escaped the kainic acid lesion in choreic monkeys as compared with the corresponding area on the intact side. It is, therefore, assumed that certain populations of 'activated' nigrostriatal dopaminergic neurons which innervate the unlesioned area of the striatum may be more likely to attain a level of activity, induced by L-DOPA, sufficient to produce choreic movements in the contralateral limbs. Methamphetamine, but not apomorphine, given to 2 monkeys, produced an effect that was essentially the same as that of L-DOPA. These results support the hypothesis that the 'activated' dopaminergic components in choreic monkeys are the presynaptic dopaminergic nerve terminals rather than the postsynaptic dopaminergic receptors.
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Electrical activity was recorded from single cells in the thalamus of 10 patients with chronic pain associated with deafferentation. Under local anesthesia, these patients underwent either electrode implantation or thalamotomy for treatment of their pain. In eight of the 10 patients, single units were identified as discharging spontaneously in high-frequency, often rhythmic, bursts. The discharges were of two types: short bursts comprised of two to six spikes with a burst frequency of one to four per second; and long trains of 30 to 80 spikes of similar frequency. Reconstruction of electrode trajectories indicated that recordings were made from the region corresponding to the lateral aspect of the mediodorsal thalamic nucleus, the central lateral nucleus, a small part of the central median nucleus, and the parafascicular nucleus. In the eight patients in whom spontaneous neuronal burst activity was exhibited, it was impossible to study activity evoked by natural cutaneous stimulation due to the continuous spontaneous neuronal discharges. Both animal and human studies have suggested that pain related to deafferentation is accompanied by spontaneous hyperactivity in the dorsal horn of the spinal cord and in the ventral posterior thalamic nuclei. The authors present evidence of spontaneous neuronal hyperactivity in the intralaminar thalamic nuclei of patients with pain related to deafferentation. The findings suggest that spontaneous neuronal discharge in patients with pain related to deafferentation is more widespread in the central nervous system than has been previously appreciated. The results have important implications for the surgical treatment of chronic pain.
Article
Evoked response amplitude-level functions were measured from electrodes in the inferior colliculus of the chinchilla before and after exposure to a 2 kHz pure tone of 105 dB SPL. The exposure produced approximately 20-30 dB of permanent threshold shift from 2 to 8 kHz, but little or no hearing loss at higher or lower frequencies. Generally less than 60% of the outer hair cells were missing in the region of hearing loss. The amplitude-level functions measured at 4 and 8 kHz generally showed a loss in sensitivity at low sound levels, a reduction in the maximum amplitude and sometimes steeper than normal slopes. The amplitude-level functions measured at 2 kHz also showed a loss in sensitivity; however, the maximum amplitude was often greater than normal. Even though there was no loss in sensitivity at 0.5 kHz, the amplitude-level function was steeper than normal and the maximum amplitude of the evoked response was almost always substantially larger than normal. The enhancement of the evoked response amplitude from the inferior colliculus does not appear to originate in the cochlea, but may reflect a reorganization of neural activity in the central auditory pathway.
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Three thousand six hundred randomly selected adults in the city of Gothenburg (425,000 inhabitants) stratified by age and gender, were questioned by mail concerning tinnitus. We received 66% useful answers, 14.2% suffered from tinnitus 'often' or 'always'. Tinnitus was more common in males than in females. Tinnitus was much more common in the left than in the right ear. 2.4% of the whole population suffered from the worst severity degree, 'tinnitus plagues me all day'. Tinnitus was clearly more common with hearing loss than with subjectively normal hearing. Sleep disturbances were common and increased with tinnitus severity. A majority of the questioned subjects wanted further examination and treatment.
Article
A new hypothesis is developed concerning the origin of chronic tinnitus. It is based on an analogy between tinnitus and intractable pain, both of their causes being seen in the de-afferentation of nerve fibers. It is suggested that in the control of tinnitus the same interplay exists between large inner-hair-cell fibers, and small outer-hair-cell fibers, provided they are deafferented, that was demonstrated to exist between large and small deafferented fibers of the somato-sensory system in the control of pain.
Article
Changes in spontaneous neuronal activity of the inferior colliculus in albino guinea pigs before and after administration of sodium salicylate were analyzed. Animals were anesthetized with pentobarbital, and two microelectrodes separated by a few hundred microns were driven through the inferior colliculus. After collecting a sufficiently large sample of cells, sodium salicylate (450 mg/kg) was injected i.p. and recordings again made 2 h after the injection. Comparison of spontaneous activity recorded before and after salicylate administration revealed highly statistically significant differences (p less than 0.001). After salicylate, the mean rate of the cell population increased from 29 to 83 Hz and the median from 26 to 74 Hz. Control experiments in which sodium salicylate was replaced by saline injection revealed no statistically significant differences in cell discharges. Recordings made during the same experiments from lobulus V of the cerebellar vermis revealed no changes in response to salicylate. The observed changes in single-unit activity due to salicylate administration may represent the first systematic evidence of a tinnituslike phenomenon in animals.
Article
The electroresponsiveness of mammalian thalamic neurons was studied in a slice preparation of the guinea pig diencephalon. Although the morphology of the cells varied, their electroresponsive properties were the same. Stimulation of thalamic cells at a membrane potential more negative than--60 mV produced burst responses and stimulation of more depolarized levels produced tonic firing of fast spikes. The burst response is generated by an inactivating Ca++-conductance. It is seen as a slow Ca++-spike which in turn triggers fast Na+-spikes. The Ca++-conductance is deinactivated by hyperpolarization beyond--60 mV. The membranes of thalamic neurons contain a number of other conductances including a Ca++-dependent K+-conductance producing spike afterhyperpolarization and a non-inactivating Na+-conductance which plays an important role during tonic activity of the cells. The early part of a response to a long-lasting stimulus given at rest or at a hyperpolarized level is dominated by the burst and thus is is independent of the stimulus amplitude. During the late part of such a response the firing rate is highly dependent of the stimulus intensity. Current-frequency plots for the first inter-spike intervals after the burst during long stimuli are upward convex, but after "steady-state" is reached the plots are almost linear.
Article
The evaluation of the spontaneous activity of 471 units from the external nucleus of the IC revealed that salicylate induces an increase of the spontaneous activity and the emergence of a bursting type of activity longer than 4 spikes. For sharply tuned units, the affected cells were from the frequency range of 10-16 kHz, which corresponds to the behaviorally measured pitch of salicylate-induced tinnitus in rats. An exogenous calcium supplement, provided under the conditions shown to attenuate the behavioral manifestation of salicylate-induced tinnitus, abolished the modification of the spontaneous activity induced by salicylate. Finally, profound changes of activity were observed for cells not responding to contralateral sound. We propose that the observed long bursts of discharges represent tinnitus-related neuronal activity. The results are consistent with the hypothesis that GABA-mediated disinhibition is involved in the processing of tinnitus-related neuronal activity.
Article
1. The central auditory pathway linking the inferior colliculus (IC) and the medial geniculate body (MGB) of the thalamus consists of a segregated ventral lemniscal and dorsal non-lemniscal projection whose synaptic transmission mechanisms remain unknown. Extracellular and intracellular recordings combined with axonal tract tracing and cell staining were made from lemniscal and non-lemniscal divisions of adult rat MGB maintained acutely in in vitro explants containing parallel tectothalamic projections. 2. Biocytin deposition within the brachium of the IC revealed dense axonal fibres projecting to the MGB. Thin axonal terminals were found throughout the ventral (MGv) and dorsal (MGd) divisions of the MGB. Bushy cells with tufted or bitufted dendritic branches were primarily found in the MGv. In the MGd, cells were mainly seen as stellate neurones having a radiate dendritic arbor. 3. Electrical stimulation of the brachium of IC invariably elicits fast, excitatory synaptic potentials in both MGv and MGd cells. The evoked responses occurred monosynaptically and were exclusively mediated by glutamate acting on both N-methyl-D-aspartate (NMDA) and non-NMDA receptors. Non-lemniscal MGd neurones recorded extracellularly exhibited a strong tendency to discharge in bursts in response to brachium stimulation. In contrast, a large proportion of ventral lemniscal cells tended to discharge in single or dual spikes. Intracellularly, MGd cells, but not MGv cells, showed a predominant, slow synaptic potential mediated by NMDA receptors. 4. It is concluded that the central auditory circuitry linking the tectum and the thalamus is connected monosynaptically via glutamatergic synapses. Lemniscal and non-lemniscal thalamic neurones possess distinct response properties which cannot be accounted for by a differential transmitter system or polysynaptic delays as postulated previously.
Article
The clinical examination of patients with severe and chronic tinnitus must include associated psychological disturbances. The present paper describes traditional diagnostic methods of ENT practice as well as the Tinnitus Questionnaire (TQ) which has been evaluated in a number of studies. This instrument differentiates between emotional and cognitive distress, auditory perceptual difficulties and self-experienced intrusiveness produced by the tinnitus. The results of a German multicenter study are presented which show that the TQ can be used to demonstrate differences of tinnitus distress under different clinical conditions (e.g., ENT clinic vs psychosomatic clinic and in- vs out-patient care). The TQ can be employed for comparative studies in different tinnitus-related institutions and for the evaluation of the relative effects of different treatment approaches.
Article
Tinnitus is said to be a common complaint of workers who are exposed to noise. We studied the prevalence and characteristics of tinnitus in 647 noise-exposed workers who had been notified as cases of noise-induced deafness. One hundred and fifty-one had tinnitus, givng a prevalence of 23.3 per cent. The tinnitus was bilateral in 42.4 per cent of cases, and of high frequency in 44.4 per cent. In 23.8 per cent it was associated with other symptoms. About 30 per cent of those with tinnitus complained that it interfered with daily activities like telephone conversation and sleep. The workers with tinnitus had consistently higher hearing thresholds at both high and low frequencies than those with no tinnitus. This finding remained even after adjusting for differences in sex, age and ethnic group composition and in the noise exposure duration. Workers are often told that noise exposure causes deafness, but little is mentioned about tinnitus. Awareness of the possible occurrence of tinnitus may encourage workers to cooperate more actively in a company hearing conservation programme.
Article
The effect of systemically applied salicylate on single-unit firing activity in primary auditory cortex was investigated in six cats. A dose of 200 mg/kg sodium salicylate was administered intraperitoneally, and recordings from the same units were performed prior to application and continuously up to, on average. 6 h after administration. Local field potentials were used to track the threshold shifts and general input-output (I/O) behavior following salicylate administration. All animals showed 20-30 dB of threshold shift about 2 h after administration and showed no recovery during the following 4 h. I/O curves were invariably of the recruitment type. Significant changes were found in spontaneous firing rates for two groups of unit separately. Low-spontaneous rate units (initial firing rate < 1 spike/s) showed an increase in spontaneous rate and high-spontaneous rate units (initial firing rate > 1 spike/s) showed a decrease in spontaneous firing rate. There were no significant changes in modal and mean values for interspike-interval (ISI) histograms. The duration-to-rebound peak in the autocorrelation function for spontaneous firings was prolonged significantly after salicylate administration. Peak cross-correlation coefficients for the firing patterns of simultaneously recorded cells showed no significant change but the correlogram's central peak was significantly narrower after salicylate application. The percentage of firings occurring in bursts showed no significant change after administration of salicylate. The best modulation frequency in response to stimulation with periodic click trains decreased after administration. Both the changes in the spontaneous autocorrelogram and in the temporal modulation transfer function suggest a prolongation in the duration of the Ca(2+)-activated K+ conductance of the cortical pyramidal cells following salicylate. This suggests that salicylates affect both the auditory periphery and the auditory cortex.
Article
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.
Article
In neurons of the auditory thalamus, patterned sequences of action potentials encode the features of sound stimuli. The patterns vary with the membrane potential, characterizing states of wakefulness and sleep. We studied the dependence of the patterns on the membrane potential and specific voltage-gated conductances, using whole-cell patch-clamp recordings from neurons in the ventral medial geniculate body (MGBv) of in vitro slices. Thalamocortical neurons, identified with neurobiotin, exhibited different firing patterns to an excitatory input, depending on the initial membrane potential. From depolarized potentials, the neurons fired in a tonic mode. The delay to firing in this mode was regulated by a balance of persistent Na+ and A-type K+ conductances. When transiently depolarized from hyperpolarized holding potentials, the neurons fired brief phasic responses (burst mode). Phasic responses were induced by low threshold Ca2+ spikes (LTSs); the LTS-amplitude was controlled by Na+ and K+ conductances. Under favourable conditions, an LTS triggered more than one action potential and one or more high threshold Ca2+ spikes (HTSs). Consciously perceived sound signals are transmitted in the tonic mode. During sleep, alerting stimuli may interact with membrane non-linearities, converting hyperpolarized bursting MGBv neurons to the tonic mode.
Article
It has been proposed that parkinsonian tremor is produced either by the activity of an intrinsic thalamic pacemaker or by the oscillation of an unstable long loop reflex arc. The former (central) hypothesis proposes that overactivity of neurons in the internal segment of the globus pallidus inhibits or hyperpolarizes thalamic neurons. When hyperpolarized, thalamic cells oscillate with bursting of the type associated with low threshold calcium spikes (low threshold spike-bursts). Low threshold spike-bursts can be identified by particular patterns of interspike intervals within the burst. The alternative (peripheral) hypothesis proposes that tremor results from oscillation of a reflex arc transmitting activity from muscle stretch receptors to thalamus, motor cortex, and back to the stretched muscle. When the gain of this reflex is increased, the arc may become unstable and oscillate. Oscillations produced by peripheral inputs may produce an acceleration-deceleration pattern within the burst which results in sinusoidal modulation of a spike train if bursting is periodic. We have assessed these two hypotheses by studying the pattern of interspike intervals occurring with burst recorded in patients with parkinsonsian tremor.
Article
This study presents firing rates for simultaneously recorded spontaneous and stimulus driven multi-unit activity in primary auditory cortex (AI), anterior auditory field (AAF) and secondary auditory cortex (AII) in cats before and after application of salicylate or quinine. From 21 cats, in three cortical areas simultaneously, a total of 1533 multi-unit files were obtained. The data suggest (1) that both salicylate and quinine significantly increase spontaneous firing rates in AII, whereas in AI and AAF both quinine and salicylate reduced the spontaneous rate; (2) the effect of both drugs was to increase spontaneous rates for recording sites with high characteristic frequency (CF) and a tendency to decrease them for low CF sites; (3) the mean stimulus driven firing rates were not affected by either drug except for a decrease produced by quinine in AI; (4) changes in driven firing rate were positively correlated with changes in spontaneous firing rates. This suggests that tinnitus inducing agents selectively increase spontaneous firing rates in the extralemniscal pathway.
Article
Thalamic neuronal activity has not been studied in a primate model of peripheral nerve injury. We now report neuronal activity in the region of the human principal sensory nucleus of thalamus (ventralis caudalis) in awake patients during the physiologic exploration that precedes surgical procedures for treatment of stump pain and movement disorders. All patients with amputations showed increased thalamic representations of the stump as reflected in both receptive and projected field maps. This suggested that thalamic re-organization involved both the afferent inputs from and the perceptual representation of the limb. The spontaneous activity of neurons in the region of ventralis caudalis representing the limb with the stump (stump area) was significantly different from that in other areas of the region of ventralis caudalis in patients with amputations (stump control areas) and in patients with movement disorders (control areas). The mean interspike intervals were significantly shorter for cells located in stump areas than for those located in stump control or control areas. Cells in all areas were found to fire in three different patterns: B group (burst) characterized by bursting activity, R group (relay) characterized as a Poisson process, and III group characterized by non-bursting, non-Poisson activity. Cells in the B group were significantly more common in stump control (41%) and stump areas (33%) than in control areas (15%). Bursting cells were found to have patterns consistent with the occurrence of a calcium spike (spike-burst pattern). The spike-burst pattern was most common among cells with receptive fields in the stump area. In these cells firing between bursts (primary event rate) was significantly higher than other cells in the region of ventralis caudalis, suggesting that spike-bursts are not due to hyperpolarization, i.e. low-threshold spikes. Spike-bursts often occur as a result of low-threshold spikes, when the cell is hyperpolarized. In contrast, spike-bursts in these patients were associated with increased interburst firing rates in cells with receptive fields. Thus bursting of these cells may have been due to high-threshold dendritic calcium spikes evoked by afferent input. In that case bursting could be involved in activity-dependent changes in thalamic function following deafferentation through a calcium-mediated mechanism.
Article
Review reports of randomized clinical trials (RCTs) in tinnitus to identify well-established treatments, promising developments, and opportunities for improvement in this area of clinical research. Literature review of RCTs (1964-1998) identified by MEDLINE and OLD MEDLINE searches and personal files. Studies were compared with the RCT criteria of Guyatt et al. for quality of design, performance, and analysis; "positive" results were critically examined for potential clinical relevance. Sixty-nine RCTs evaluated tocainide and related drugs, carbamazepine, benzodiazepines, tricyclic antidepressants, 16 miscellaneous drugs, psychotherapy, electrical/magnetic stimulation, acupuncture, masking, biofeedback, hypnosis, and miscellaneous other nondrug treatments. No treatment can yet be considered well established in terms of providing replicable long-term reduction of tinnitus impact, in excess of placebo effects. Nonspecific support and counseling are probably helpful, as are tricyclic antidepressants in severe cases. Benzodiazepines, newer antidepressants, and electrical stimulation deserve further study. Future tinnitus therapeutic research should emphasize adequate sample size, open trials before RCTs, careful choice of outcome measures, and long-term follow-up.
Article
The inferior colliculus is a central auditory structure which serves as a site for the integration of ascending and descending auditory information. Changes in central auditory structures may occur with acoustic exposure, which cannot be explained by alterations in cochlear function alone. Rats were exposed to a 10-kHz tone at 100 dB SPL for 9 h. Auditory brainstem response measures showed an initial 25-30-dB threshold shift across all tested frequencies. By 30 days post-exposure, thresholds for clicks and most frequencies returned to near control levels; however, thresholds remained elevated at 10 and 20 kHz. Inner hair cell loss was confined to apical and basal ends of the cochlea, and did not exceed 20%. Inferior colliculus levels of the two isoforms of the GABA synthetic enzyme glutamate decarboxylase (65,000 and 67,000 mol. wt forms) were measured immediately post-exposure (0 h) and at two and 30 days post-exposure using quantitative immunocytochemical and western blotting techniques. Zero-hour measures revealed a significant increase in the level of glutamate decarboxylase (mol. wt 67,000) protein (118%), as well as in the optical density (35%) of immunolabeled cells. By 30 days post-exposure, inferior colliculus protein levels of both glutamate decarboxylase isoforms were significantly below unexposed controls (39% and 21% for the 65,000 and 67,000 mol. wt forms, respectively). These studies describe increased markers for GABA immediately following acoustic exposure, followed by a decline to below control levels from two to 30 days post-exposure. It remains to be determined whether noise trauma-induced changes in glutamate decarboxylase levels in the inferior colliculus reflect protective up-regulation in response to intense stimulation, followed by the establishment of new neurotransmitter equilibrium levels.