Consensus for tinnitus patient assessment and treatment outcome measurement: Tinnitus Research Initiative meeting, Regensburg, July 2006.

There is widespread recognition that consistency between research centres in the ways that patients with tinnitus are assessed and outcomes following interventions are measured would facilitate more effective co-operation and more meaningful evaluations and comparisons of outcomes. At the first Tinnitus Research Initiative meeting held in Regensburg in July 2006 an attempt was made through workshops to gain a consensus both for patient assessments and for outcome measurements. It is hoped that this will contribute towards better cooperation between research centres in finding and evaluating treatments for tinnitus by allowing better comparability between studies.

Structural brain changes in tinnitus.

Tinnitus is a common but poorly understood disorder characterized by ringing or buzzing in the ear. Central mechanisms must play a crucial role in generating this auditory phantom sensation as it persists in most cases after severing the auditory nerve. One hypothesis states that tinnitus is caused by a reorganization of tonotopic maps in the auditory cortex, which leads to an overrepresentation of tinnitus frequencies. Moreover, the participation of the limbic system in generating tinnitus has been postulated. Here we aimed at identifying brain areas that display structural change in tinnitus. We compared tinnitus sufferers with healthy controls by using high-resolution magnetic resonance imaging and voxel-based morphometry. Within the auditory pathways, we found gray-matter increases only at the thalamic level. Outside the auditory system, gray-matter decrease was found in the subcallosal region including the nucleus accumbens. Our results suggest that reciprocal involvement of both sensory and emotional areas are essential in the generation of tinnitus.

Sending sound to the brain.

The cochlear implant, a microelectrode array that directly stimulates the auditory nerve, has greatly benefited many individuals with profound deafness. Deaf patients without an intact auditory nerve may be helped by the next generation of auditory prostheses: surface or penetrating auditory brainstem implants that bypass the auditory nerve and directly stimulate auditory processing centers in the brainstem.

Cortical plasticity and music.

Auditory experience changes the make-up of areas in the cerebral cortex that are involved in the processing of complex sounds, including music. Evidence for this comes from various lines of research. Early blindness results in an expansion of auditory-responsive areas in the parietal cortex and a refinement in the selectivity of neurons in the auditory cortex. Occipital areas normally used only for vision are activated by auditory stimuli in the early blind. This lends credibility to the claim that blind individuals have greater musical abilities. The cross-modal changes in auditory cortical representations are based on activity-dependent modifications of synaptic circuitry. Imagery and anticipation of music also lead to activation of the auditory (and frontal) cortex. It is conceivable, therefore, that even with mental practice alone we can sharpen our musical representations in the cerebral cortex.

Functional specialization in rhesus monkey auditory cortex.

Neurons in the lateral belt areas of rhesus monkey auditory cortex prefer complex sounds to pure tones, but functional specializations of these multiple maps in the superior temporal region have not been determined. We tested the specificity of neurons in the lateral belt with species-specific communication calls presented at different azimuth positions. We found that neurons in the anterior belt are more selective for the type of call, whereas neurons in the caudal belt consistently show the greatest spatial selectivity. These results suggest that cortical processing of auditory spatial and pattern information is performed in specialized streams rather than one homogeneously distributed system.

Hierarchical organization of the human auditory cortex revealed by functional magnetic resonance imaging.

The concept of hierarchical processing--that the sensory world is broken down into basic features later integrated into more complex stimulus preferences--originated from investigations of the visual cortex. Recent studies of the auditory cortex in nonhuman primates revealed a comparable architecture, in which core areas, receiving direct input from the thalamus, in turn, provide input to a surrounding belt. Here functional magnetic resonance imaging (fMRI) shows that the human auditory cortex displays a similar hierarchical organization: pure tones (PTs) activate primarily the core, whereas belt areas prefer complex sounds, such as narrow-band noise bursts.

Mechanisms and streams for processing of "what" and "where" in auditory cortex.

The functional specialization and hierarchical organization of multiple areas in rhesus monkey auditory cortex were examined with various types of complex sounds. Neurons in the lateral belt areas of the superior temporal gyrus were tuned to the best center frequency and bandwidth of band-passed noise bursts. They were also selective for the rate and direction of linear frequency modulated sweeps. Many neurons showed a preference for a limited number of species-specific vocalizations ("monkey calls"). These response selectivities can be explained by nonlinear spectral and temporal integration mechanisms. In a separate series of experiments, monkey calls were presented at different spatial locations, and the tuning of lateral belt neurons to monkey calls and spatial location was determined. Of the three belt areas the anterolateral area shows the highest degree of specificity for monkey calls, whereas neurons in the caudolateral area display the greatest spatial selectivity. We conclude that the cortical auditory system of primates is divided into at least two processing streams, a spatial stream that originates in the caudal part of the superior temporal gyrus and projects to the parietal cortex, and a pattern or object stream originating in the more anterior portions of the lateral belt. A similar division of labor can be seen in human auditory cortex by using functional neuroimaging.

A positron emission tomographic study of auditory localization in the congenitally blind.

We have used positron emission tomography (PET) to measure regional cerebral blood flow (rCBF) in sighted and congenitally blind subjects performing auditory localization tasks. During scanning, the spectral and binaural cues of localized sound were reproduced by a sound system and delivered via headphones. During tasks that required auditory localization both the sighted and blind subjects strongly activated posterior parietal areas. In addition, the blind subjects activated association areas in the right occipital cortex, the foci of which were similar to areas previously identified in visual location and motion detection experiments in sighted subjects. The blind subjects, therefore, demonstrated visual to auditory cross-modal plasticity with auditory localization activating occipital association areas originally intended for dorsal-stream visual processing. To determine the functional connectivity of pre-selected brain regions in primary and non-primary auditory and posterior parietal cortex in the two cohorts, we performed an inter-regional correlation analysis on the rCBF data set. During auditory localization in the blind subjects, rCBF activity in the right posterior parietal cortex was positively correlated with that in the right occipital region, whereas in sighted subjects correlations were generally negative. There were no significant positive occipital correlations in either cohort when reference regions in temporal or left parietal cortex were chosen. This indicates that in congenitally blind subjects the right occipital cortex participates in a functional network for auditory localization and that occipital activity is more likely to arise from connections with posterior parietal cortex.

Dual streams of auditory afferents target multiple domains in the primate prefrontal cortex.

'What' and 'where' visual streams define ventrolateral object and dorsolateral spatial processing domains in the prefrontal cortex of nonhuman primates. We looked for similar streams for auditory-prefrontal connections in rhesus macaques by combining microelectrode recording with anatomical tract-tracing. Injection of multiple tracers into physiologically mapped regions AL, ML and CL of the auditory belt cortex revealed that anterior belt cortex was reciprocally connected with the frontal pole (area 10), rostral principal sulcus (area 46) and ventral prefrontal regions (areas 12 and 45), whereas the caudal belt was mainly connected with the caudal principal sulcus (area 46) and frontal eye fields (area 8a). Thus separate auditory streams originate in caudal and rostral auditory cortex and target spatial and non-spatial domains of the frontal lobe, respectively.

Modality-specific frontal and parietal areas for auditory and visual spatial localization in humans.

Although the importance of the posterior parietal and prefrontal regions in spatial localization of visual stimuli is well established, their role in auditory space perception is less clear. Using positron emission tomography (PET) during auditory and visual spatial localization in the same subjects, modality-specific areas were identified in the superior parietal lobule, middle temporal and lateral prefrontal cortices. These findings suggest that, similar to the visual system, the hierarchical organization of the auditory system extends beyond the temporal lobe to include areas in the posterior parietal and prefrontal regions specialized in auditory spatial processing. Our results may explain the dissociation of visual and auditory spatial localization deficits following lesions involving these regions.

A PET study of human auditory spatial processing.

To learn more about human auditory spatial processing, we used positron emission tomography (PET) to measure regional cerebral blood flow in human volunteers engaged in sound localization tasks. Spectral and binaural cues of localized sound were reproduced by a sound system and delivered via headphones. During localization tasks, subjects activated inferior parietal lobules (IPL) bilaterally. In a second experiment, matched in design to the first, subjects made non-spatial auditory discriminations based on frequency, activating the IPL bilaterally with left hemispheric predominance. A between-study comparison revealed that the right IPL was significantly more activated during the sound localization task compared with the feature discrimination task, suggesting a preferential role for the right IPL in auditory spatial processing.

Auditory cortical plasticity: a comparison with other sensory systems.

The auditory cortex has a crucial role in higher cognitive functions, including the perception of speech, music and auditory space. Cortical plasticity, as in other sensory systems, is used in the fine tuning of the auditory system for these higher functions. Auditory cortical plasticity can also be demonstrated after lesions of the cochlea and it appears to participate in generating tinnitus. Early musical training leads to an expansion in the representation of complex harmonic sounds in the auditory cortex. Similarly, the early phonetic environment has a strong influence on speech development and, presumably, on the cortical organization of speech. In auditory spatial perception, the spectral cues generated by the head and outer ears vary between individuals and have to be calibrated by learning, which most probably takes place at the cortical level. The neural mechanisms of plasticity are likely to be the same across all cortical regions. It should be useful, therefore, to relate some of the findings and hypotheses about auditory cortical plasticity to previous studies of other sensory systems.

Cortical processing of complex sounds.

Work on the functional organization of auditory cortex in nonhuman primates has recently gained increasing attention. Neurophysiological studies using complex stimuli, combined with anatomical tract tracing, reveal a hierarchy of cortical processing comparable to other sensory systems. On the basis of these findings from animal studies, together with the advent of modern neuroimaging methods used in human cortex, the field of auditory neuroscience could soon arrive at a detailed understanding of the cortical representation of complex sounds, including speech.

Hemispheric specialization for English and ASL: left invariance-right variability.

Functional magnetic resonance imaging (fMRI) was used to compare the cerebral organization during sentence processing in English and in American sign language (ASL). Classical language areas within the left hemisphere were recruited by both English in native speakers and ASL in native signers. This suggests a bias of the left hemisphere to process natural languages independently of the modality through which language is perceived. Furthermore, in contrast to English, ASL strongly recruited right hemisphere structures. This was true irrespective of whether the native signers were deaf or hearing. Thus, the specific processing requirements of the language also in part determine the organization of the language systems of the brain.

Processing of frequency-modulated sounds in the cat's posterior auditory field.

Single-neuron activity was recorded from the posterior auditory field (PAF) in the cortex of gas-anesthetized cats. Tone bursts and broadband complex sounds were used for auditory stimulation. Responses to frequency-modulated (FM) sounds, in particular, were studied systematically. Linear FM sweeps were centered around the best frequency (BF) of a neuron and had an excursion large enough to cover its whole frequency tuning range. Rate and direction of change of the FM sweeps were varied. In the majority of PAF neurons (75%) the FM response seemed not to be linear, i.e., their best instantaneous frequency (BIF) varied by more than one octave at different FM rates (FMR). When the difference between BIF and BF at each FMR was used as a measure of linearity, it was within one-third octave only at five or fewer FMR in most PAF neurons (74%). The majority of PAF neurons (70%) preferred moderate FM rates (<200 Hz/ms). Fifty-four percent of all neurons in this area showed band-pass behavior with a clear preference in the middle range of FM rates in at least one direction. Overall, neurons with high-pass behavior in both directions made up only a minor portion (22%) of PAF neurons. When both directions of an FM sweep (low-to-high and high-to-low frequency) were tested, 50% of the neurons were clearly selective for one direction, i.e., the response to one FM direction was at least twice as large as that to the other direction. This selectivity was not necessarily present at the preferred FM rate. In general, FM direction selectivity was equally distributed over FM rates tested. The selectivity of PAF neurons for the rate and direction of FM sounds makes these neurons suitable for the detection and analysis of communication sounds, which often contain FM components with a moderate sweep rate in a particular direction.

Parallel processing in the auditory cortex of primates.

Evidence from anatomical tracer studies as well as lesions of the primary auditory cortex (AI) indicate that the principal relay nucleus of the auditory thalamus, the ventral part of the medial geniculate (MGv), projects in parallel to AI and the rostral area on the supratemporal plane of the macaque monkey. The caudomedial area, by contrast, receives input from MGv only indirectly via AI, and neurons in this area are often tuned to the spatial location of a complex sound. The belt areas on the lateral surface of the superior temporal gyrus receive input from the primary areas. Neurons in these areas respond better to more complex stimuli, such as band-pass noise pulses of frequency-modulated sweeps, than to pure tones. Often neurons in the lateral belt respond well to species-specific communication calls. The hypothesis is put forward that the central auditory pathways in the macaque monkey are organized into parallel streams, similar to the visual system, one for the processing of spatial information, the other for the processing of auditory "patterns". Evidence from neuroimaging studies in humans with MRI and PET are consistent with this hypothesis. Virtual auditory space stimuli lead to selective activation of an inferior parietal region, whereas speech-like stimuli activate superior temporal regions.

An in vivo model for functional MRI in cat visual cortex.

A protocol is described for obtaining functional magnetic resonance images in anesthetized cat brain based on the blood oxygenation level dependent (BOLD) contrast mechanism. A visual stimulus was used, which consisted of a high-contrast drifting grating, whose speed and spatial frequency was optimized for cat area 18 (V2). Experiments were conducted at 4.7 Tesla using a gradient echo EPI sequence with a 29-ms echo time, yielding signal changes of between 0.7% and 2% in area 18.

Attention-related modulation of activity in primary and secondary auditory cortex.

We investigated the effects of auditory attention on brain activity using functional magnetic resonance imaging. Subjects listened to three word lists, three times each, and were instructed to count the number of times they heard a target word during two of these presentations. For the third, they listened to the words without counting. All subjects showed significant areas of activation in auditory cortex during the listening conditions compared to rest. There was significantly more activation and a larger area of activation, particularly in association cortex, in the left temporal lobe during counting of targets compared to the no-target conditions, with a similar trend in the right hemisphere. These results provide evidence of an attention-related enhancement of both activation magnitude and extent in auditory cortex.