An energy costly architecture of neuromodulators for human brain evolution and cognition.

In comparison to other species, the human brain exhibits one of the highest energy demands relative to body metabolism. It remains unclear whether this heightened energy demand uniformly supports an enlarged brain or if specific signaling mechanisms necessitate greater energy. We hypothesized that the regional distribution of energy demands will reveal signaling strategies that have contributed to human cognitive development. We measured the energy distribution within the brain functional connectome using multimodal brain imaging and found that signaling pathways in evolutionarily expanded regions have up to 67% higher energetic costs than those in sensory-motor regions. Additionally, histology, transcriptomic data, and molecular imaging independently reveal an up-regulation of signaling at G-protein-coupled receptors in energy-demanding regions. Our findings indicate that neuromodulator activity is predominantly involved in cognitive functions, such as reading or memory processing. This study suggests that an up-regulation of neuromodulator activity, alongside increased brain size, is a crucial aspect of human brain evolution.

Anatomy of the auditory cortex then and now.

Using neuroanatomical investigations in the macaque, Deepak Pandya and his colleagues have established the framework for auditory cortex organization, with subdivisions into core and belt areas. This has aided subsequent neurophysiological and imaging studies in monkeys and humans, and a nomenclature building on Pandya's work has also been adopted by the Human Connectome Project. The foundational work by Pandya and his colleagues is highlighted here in the context of subsequent and ongoing studies on the functional anatomy and physiology of auditory cortex in primates, including humans, and their relevance for understanding cognitive aspects of speech and language.

Sound-encoded faces activate the left fusiform face area in the early blind.

Face perception in humans and nonhuman primates is accomplished by a patchwork of specialized cortical regions. How these regions develop has remained controversial. In sighted individuals, facial information is primarily conveyed via the visual modality. Early blind individuals, on the other hand, can recognize shapes using auditory and tactile cues. Here we demonstrate that such individuals can learn to distinguish faces from houses and other shapes by using a sensory substitution device (SSD) presenting schematic faces as sound-encoded stimuli in the auditory modality. Using functional MRI, we then asked whether a face-selective brain region like the fusiform face area (FFA) shows selectivity for faces in the same subjects, and indeed, we found evidence for preferential activation of the left FFA by sound-encoded faces. These results imply that FFA development does not depend on experience with visual faces per se but may instead depend on exposure to the geometry of facial configurations.

Evidence for a Spoken Word Lexicon in the Auditory Ventral Stream.

The existence of a neural representation for whole words (i.e., a lexicon) is a common feature of many models of speech processing. Prior studies have provided evidence for a visual lexicon containing representations of whole written words in an area of the ventral visual stream known as the visual word form area. Similar experimental support for an auditory lexicon containing representations of spoken words has yet to be shown. Using functional magnetic resonance imaging rapid adaptation techniques, we provide evidence for an auditory lexicon in the auditory word form area in the human left anterior superior temporal gyrus that contains representations highly selective for individual spoken words. Furthermore, we show that familiarization with novel auditory words sharpens the selectivity of their representations in the auditory word form area. These findings reveal strong parallels in how the brain represents written and spoken words, showing convergent processing strategies across modalities in the visual and auditory ventral streams.

Listening to familiar music induces continuous inhibition of alpha and low-beta power.

How the brain responds temporally and spectrally when we listen to familiar versus unfamiliar musical sequences remains unclear. This study uses EEG techniques to investigate the continuous electrophysiological changes in the human brain during passive listening to familiar and unfamiliar musical excerpts. EEG activity was recorded in 20 participants while they passively listened to 10 s of classical music, and they were then asked to indicate their self-assessment of familiarity. We analyzed the EEG data in two manners: familiarity based on the within-subject design, i.e., averaging trials for each condition and participant, and familiarity based on the same music excerpt, i.e., averaging trials for each condition and music excerpt. By comparing the familiar condition with the unfamiliar condition and the local baseline, sustained low-beta power (12-16 Hz) suppression was observed in both analyses in fronto-central and left frontal electrodes after 800 ms. However, sustained alpha power (8-12 Hz) decreased in fronto-central and posterior electrodes after 850 ms only in the first type of analysis. Our study indicates that listening to familiar music elicits a late sustained spectral response (inhibition of alpha/low-beta power from 800 ms to 10 s). Moreover, the results showed that alpha suppression reflects increased attention or arousal/engagement due to listening to familiar music; nevertheless, low-beta suppression exhibits the effect of familiarity.NEW & NOTEWORTHY This study differentiates the dynamic temporal-spectral effects during listening to 10 s of familiar music compared with unfamiliar music. This study highlights that listening to familiar music leads to continuous suppression in the alpha and low-beta bands. This suppression starts ∼800 ms after the stimulus onset.

Disruptions of default mode network and precuneus connectivity associated with cognitive dysfunctions in tinnitus.

Tinnitus is the perception of a ringing, buzzing or hissing sound "in the ear" without external stimulation. Previous research has demonstrated changes in resting-state functional connectivity in tinnitus, but findings do not overlap and are even contradictory. Furthermore, how altered functional connectivity in tinnitus is related to cognitive abilities is currently unknown. Here we investigated resting-state functional connectivity differences between 20 patients with chronic tinnitus and 20 control participants matched in age, sex and hearing loss. All participants underwent functional magnetic resonance imaging, audiometric and cognitive assessments, and filled in questionnaires targeting anxiety and depression. Significant differences in functional connectivity between tinnitus patients and control participants were not obtained. However, we did find significant associations between cognitive scores and functional coupling of the default mode network and the precuneus with the superior parietal lobule, supramarginal gyrus, and orbitofrontal cortex. Further, tinnitus distress correlated with connectivity between the precuneus and the lateral occipital complex. This is the first study providing evidence for disruptions of default mode network and precuneus coupling that are related to cognitive dysfunctions in tinnitus. The constant attempt to decrease the tinnitus sensation might occupy certain brain resources otherwise available for concurrent cognitive operations.

Auditory cortical connectivity in humans.

To understand auditory cortical processing, the effective connectivity between 15 auditory cortical regions and 360 cortical regions was measured in 171 Human Connectome Project participants, and complemented with functional connectivity and diffusion tractography. 1. A hierarchy of auditory cortical processing was identified from Core regions (including A1) to Belt regions LBelt, MBelt, and 52; then to PBelt; and then to HCP A4. 2. A4 has connectivity to anterior temporal lobe TA2, and to HCP A5, which connects to dorsal-bank superior temporal sulcus (STS) regions STGa, STSda, and STSdp. These STS regions also receive visual inputs about moving faces and objects, which are combined with auditory information to help implement multimodal object identification, such as who is speaking, and what is being said. Consistent with this being a "what" ventral auditory stream, these STS regions then have effective connectivity to TPOJ1, STV, PSL, TGv, TGd, and PGi, which are language-related semantic regions connecting to Broca's area, especially BA45. 3. A4 and A5 also have effective connectivity to MT and MST, which connect to superior parietal regions forming a dorsal auditory "where" stream involved in actions in space. Connections of PBelt, A4, and A5 with BA44 may form a language-related dorsal stream.

Increased fiber density of the fornix in patients with chronic tinnitus revealed by diffusion-weighted MRI.

Up to 45% of the elderly population suffer from chronic tinnitus - the phantom perception of sound that is often perceived as ringing, whistling, or hissing "in the ear" without external stimulation. Previous research investigated white matter changes in tinnitus patients using diffusion-weighted magnetic resonance imaging (DWI) to assess measures such as fractional anisotropy (a measure of microstructural integrity of fiber tracts) or mean diffusivity (a measure for general water diffusion). However, findings overlap only minimally and are sometimes even contradictory. We here present the first study encompassing higher diffusion data that allow to focus on changes in tissue microstructure, such as number of axons (fiber density) and macroscopic alterations, including axon diameter, and a combination of both. In order to deal with the crossing-fibers problem, we applied a fixel-based analysis using a constrained spherical deconvolution signal modeling approach. We investigated differences between tinnitus patients and control participants as well as how cognitive abilities and tinnitus distress are related to changes in white matter morphology in chronic tinnitus. For that aim, 20 tinnitus patients and 20 control participants, matched in age, sex and whether they had hearing loss or not, underwent DWI, audiometric and cognitive assessments, and filled in questionnaires targeting anxiety and depression. Our results showed increased fiber density in the fornix in tinnitus patients compared to control participants. The observed changes might, reflect compensatory structural alterations related to the processing of negative emotions or maladaptive changes related to the reinforced learning of the chronic tinnitus sensation. Due to the low sample size, the study should be seen as a pilot study that motivates further research to investigate underlying white matter morphology alterations in tinnitus.

Neuroanatomical alterations in middle frontal gyrus and the precuneus related to tinnitus and tinnitus distress.

Tinnitus is the phantom perception of sound when there is no external auditory input. This sound is mostly perceived as a ringing, whistling or buzzing in the ear. There is evidence of neural changes in both central auditory regions as well as other brain areas like the prefrontal cortex and the limbic system. However, brain morphological studies assessing gray matter volume and cortical thickness have shown inconsistent results. We here investigated neuroanatomical alterations in tinnitus related to the tinnitus perception along with tinnitus distress and cognitive abilities. Twenty tinnitus patients and 20 control participants matched in age, sex and hearing loss participated in the study. They underwent magnetic resonance imaging and audiometric as well as cognitive assessments. Our results demonstrate increased gray matter volume in the middle frontal gyrus and frontal pole in tinnitus compared to control participants. Moreover, we found increased cortical thickness in the precuneus associated with tinnitus distress as well as an interaction between group and cognitive assessment scores in cortical thickness of the middle frontal gyrus, indicating higher cortical thickness with better scores in controls and lower scores in tinnitus patients. These findings indicate that increased tinnitus awareness and annoyance is reflected in increased brain structural changes in the precuneus, frontal pole and middle frontal gyrus that may also have implications on general cognitive abilities.

The blinking eye as a window into tinnitus: A new animal model of tinnitus in the macaque.

Tinnitus is a highly prevalent, largely untreatable auditory disorder, characterized by the perception of phantom sound often in the form of incessant ringing or hissing. Despite longstanding research with animal models, its underlying pathophysiological causes remain poorly understood. Given recent data characterizing tinnitus as a disorder with a strong neurocognitive component, progress in the field might be hastened by testing a wider spectrum of animal models, including nonhuman primates, and by developing alternative measurement techniques of tinnitus, especially in animals. To provide fresh impetus, we developed a novel tinnitus-verification technique applicable to rhesus monkeys. Tinnitus was induced via salicylate administration in two monkeys, and was confirmed by applying a specific eyeblink procedure: Blinks, as monitored with EMG, were triggered via puffs of air towards the cheek, and their modulation was studied as a function of preceding tones under various frequency and intensity conditions. The advantage of a tactile reflex-inducing stimulus lies in its non-auditory modality, bypassing potential confounding factors of hearing loss and hyperacusis. Interference effects on the blink modulation pattern were interpreted as tinnitus, and the frequency of the preceding interfering tone as tinnitus frequency. A cross-validation in a sample of human tinnitus patients revealed interfering effects of the preceding tone in the specific frequency range corresponding to their own tinnitus frequency, as independently determined by audiologists. This interference effect increased as a function of individual tinnitus loudness. In conclusion, the present work demonstrates considerable transferability of a newly established tinnitus-verification technique from nonhuman primates to human tinnitus patients. The technique may be usable both for objective measurements of tinnitus in human patients as well as a potential alternative technique for routine tinnitus testing in animal models.

Tinnitus and tinnitus disorder: Theoretical and operational definitions (an international multidisciplinary proposal).

As for hypertension, chronic pain, epilepsy and other disorders with particular symptoms, a commonly accepted and unambiguous definition provides a common ground for researchers and clinicians to study and treat the problem. The WHO's ICD11 definition only mentions tinnitus as a nonspecific symptom of a hearing disorder, but not as a clinical entity in its own right, and the American Psychiatric Association's DSM-V doesn't mention tinnitus at all. Here we propose that the tinnitus without and with associated suffering should be differentiated by distinct terms: "Tinnitus" for the former and "Tinnitus Disorder" for the latter. The proposed definition then becomes "Tinnitus is the conscious awareness of a tonal or composite noise for which there is no identifiable corresponding external acoustic source, which becomes Tinnitus Disorder "when associated with emotional distress, cognitive dysfunction, and/or autonomic arousal, leading to behavioural changes and functional disability.". In other words "Tinnitus" describes the auditory or sensory component, whereas "Tinnitus Disorder" reflects the auditory component and the associated suffering. Whereas acute tinnitus may be a symptom secondary to a trauma or disease, chronic tinnitus may be considered a primary disorder in its own right. If adopted, this will advance the recognition of tinnitus disorder as a primary health condition in its own right. The capacity to measure the incidence, prevalence, and impact will help in identification of human, financial, and educational needs required to address acute tinnitus as a symptom but chronic tinnitus as a disorder.

Effective connectivity in the default mode network is distinctively disrupted in Alzheimer's disease-A simultaneous resting-state FDG-PET/fMRI study.

A prominent finding of postmortem and molecular imaging studies on Alzheimer's disease (AD) is the accumulation of neuropathological proteins in brain regions of the default mode network (DMN). Molecular models suggest that the progression of disease proteins depends on the directionality of signaling pathways. At network level, effective connectivity (EC) reflects directionality of signaling pathways. We hypothesized a specific pattern of EC in the DMN of patients with AD, related to cognitive impairment. Metabolic connectivity mapping is a novel measure of EC identifying regions of signaling input based on neuroenergetics. We simultaneously acquired resting-state functional MRI and FDG-PET data from patients with early AD (n = 35) and healthy subjects (n = 18) on an integrated PET/MR scanner. We identified two distinct subnetworks of EC in the DMN of healthy subjects: an anterior part with bidirectional EC between hippocampus and medial prefrontal cortex and a posterior part with predominant input into medial parietal cortex. Patients had reduced input into the medial parietal system and absent input from hippocampus into medial prefrontal cortex (p < 0.05, corrected). In a multiple linear regression with unimodal imaging and EC measures (F4,25 = 5.63, p = 0.002, r2 = 0.47), we found that EC (ß = 0.45, p = 0.012) was stronger associated with cognitive deficits in patients than any of the PET and fMRI measures alone. Our approach indicates specific disruptions of EC in the DMN of patients with AD and might be suitable to test molecular theories about downstream and upstream spreading of neuropathology in AD.

Inter-subject Similarity of Brain Activity in Expert Musicians After Multimodal Learning: A Behavioral and Neuroimaging Study on Learning to Play a Piano Sonata.

Human behavior is inherently multimodal and relies on sensorimotor integration. This is evident when pianists exhibit activity in motor and premotor cortices, as part of a dorsal pathway, while listening to a familiar piece of music, or when naïve participants learn to play simple patterns on the piano. Here we investigated the interaction between multimodal learning and dorsal-stream activity over the course of four weeks in ten skilled pianists by adopting a naturalistic data-driven analysis approach. We presented the pianists with audio-only, video-only and audiovisual recordings of a piano sonata during functional magnetic resonance imaging (fMRI) before and after they had learned to play the sonata by heart for a total of four weeks. We followed the learning process and its outcome with questionnaires administered to the pianists, one piano instructor following their training, and seven external expert judges. The similarity of the pianists' brain activity during stimulus presentations was examined before and after learning by means of inter-subject correlation (ISC) analysis. After learning, an increased ISC was found in the pianists while watching the audiovisual performance, particularly in motor and premotor regions of the dorsal stream. While these brain structures have previously been associated with learning simple audio-motor sequences, our findings are the first to suggest their involvement in learning a complex and demanding audiovisual-motor task. Moreover, the most motivated learners and the best performers of the sonata showed ISC in the dorsal stream and in the reward brain network.

Auditory representation of learned sound sequences in motor regions of the macaque brain.

Human speech production requires the ability to couple motor actions with their auditory consequences. Nonhuman primates might not have speech because they lack this ability. To address this question, we trained macaques to perform an auditory-motor task producing sound sequences via hand presses on a newly designed device ("monkey piano"). Catch trials were interspersed to ascertain the monkeys were listening to the sounds they produced. Functional MRI was then used to map brain activity while the animals listened attentively to the sound sequences they had learned to produce and to two control sequences, which were either completely unfamiliar or familiar through passive exposure only. All sounds activated auditory midbrain and cortex, but listening to the sequences that were learned by self-production additionally activated the putamen and the hand and arm regions of motor cortex. These results indicate that, in principle, monkeys are capable of forming internal models linking sound perception and production in motor regions of the brain, so this ability is not special to speech in humans. However, the coupling of sounds and actions in nonhuman primates (and the availability of an internal model supporting it) seems not to extend to the upper vocal tract, that is, the supralaryngeal articulators, which are key for the production of speech sounds in humans. The origin of speech may have required the evolution of a "command apparatus" similar to the control of the hand, which was crucial for the evolution of tool use.

Effects of age and left hemisphere lesions on audiovisual integration of speech.

Neuroimaging studies have implicated left temporal lobe regions in audiovisual integration of speech and inferior parietal regions in temporal binding of incoming signals. However, it remains unclear which regions are necessary for audiovisual integration, especially when the auditory and visual signals are offset in time. Aging also influences integration, but the nature of this influence is unresolved. We used a McGurk task to test audiovisual integration and sensitivity to the timing of audiovisual signals in two older adult groups: left hemisphere stroke survivors and controls. We observed a positive relationship between age and audiovisual speech integration in both groups, and an interaction indicating that lesions reduce sensitivity to timing offsets between signals. Lesion-symptom mapping demonstrated that damage to the left supramarginal gyrus and planum temporale reduces temporal acuity in audiovisual speech perception. This suggests that a process mediated by these structures identifies asynchronous audiovisual signals that should not be integrated.

Cortical mechanisms of spatial hearing.

Humans and other animals use spatial hearing to rapidly localize events in the environment. However, neural encoding of sound location is a complex process involving the computation and integration of multiple spatial cues that are not represented directly in the sensory organ (the cochlea). Our understanding of these mechanisms has increased enormously in the past few years. Current research is focused on the contribution of animal models for understanding human spatial audition, the effects of behavioural demands on neural sound location encoding, the emergence of a cue-independent location representation in the auditory cortex, and the relationship between single-source and concurrent location encoding in complex auditory scenes. Furthermore, computational modelling seeks to unravel how neural representations of sound source locations are derived from the complex binaural waveforms of real-life sounds. In this article, we review and integrate the latest insights from neurophysiological, neuroimaging and computational modelling studies of mammalian spatial hearing. We propose that the cortical representation of sound location emerges from recurrent processing taking place in a dynamic, adaptive network of early (primary) and higher-order (posterior-dorsal and dorsolateral prefrontal) auditory regions. This cortical network accommodates changing behavioural requirements and is especially relevant for processing the location of real-life, complex sounds and complex auditory scenes.

Overlapping Anatomical Networks Convey Cross-Modal Suppression in the Sighted and Coactivation of "Visual" and Auditory Cortex in the Blind.

In the present combined DTI/fMRI study we investigated adaptive plasticity of neural networks involved in controlling spatial and nonspatial auditory working memory in the early blind (EB). In both EB and sighted controls (SC), fractional anisotropy (FA) within the right inferior longitudinal fasciculus correlated positively with accuracy in a one-back sound localization but not sound identification task. The neural tracts passing through the cluster of significant correlation connected auditory and "visual" areas in the right hemisphere. Activity in these areas during both sound localization and identification correlated with FA within the anterior corpus callosum, anterior thalamic radiation, and inferior fronto-occipital fasciculus. In EB, FA in these structures correlated positively with activity in both auditory and "visual" areas, whereas FA in SC correlated positively with activity in auditory and negatively with activity in visual areas. The results indicate that frontal white matter conveys cross-modal suppression of occipital areas in SC, while it mediates coactivation of auditory and reorganized "visual" cortex in EB.

Distinct brain areas process novel and repeating tone sequences.

The auditory dorsal stream has been implicated in sensorimotor integration and concatenation of sequential sound events, both being important for processing of speech and music. The auditory ventral stream, by contrast, is characterized as subserving sound identification and recognition. We studied the respective roles of the dorsal and ventral streams, including recruitment of basal ganglia and medial temporal lobe structures, in the processing of tone sequence elements. A sequence was presented incrementally across several runs during functional magnetic resonance imaging in humans, and we compared activation by sequence elements when heard for the first time ("novel") versus when the elements were repeating ("familiar"). Our results show a shift in tone-sequence-dependent activation from posterior-dorsal cortical areas and the basal ganglia during the processing of less familiar sequence elements towards anterior and ventral cortical areas and the medial temporal lobe after the encoding of highly familiar sequence elements into identifiable auditory objects.

Active Sound Localization Sharpens Spatial Tuning in Human Primary Auditory Cortex.

Spatial hearing sensitivity in humans is dynamic and task-dependent, but the mechanisms in human auditory cortex that enable dynamic sound location encoding remain unclear. Using functional magnetic resonance imaging (fMRI), we assessed how active behavior affects encoding of sound location (azimuth) in primary auditory cortical areas and planum temporale (PT). According to the hierarchical model of auditory processing and cortical functional specialization, PT is implicated in sound location ("where") processing. Yet, our results show that spatial tuning profiles in primary auditory cortical areas (left primary core and right caudo-medial belt) sharpened during a sound localization ("where") task compared with a sound identification ("what") task. In contrast, spatial tuning in PT was sharp but did not vary with task performance. We further applied a population pattern decoder to the measured fMRI activity patterns, which confirmed the task-dependent effects in the left core: sound location estimates from fMRI patterns measured during active sound localization were most accurate. In PT, decoding accuracy was not modulated by task performance. These results indicate that changes of population activity in human primary auditory areas reflect dynamic and task-dependent processing of sound location. As such, our findings suggest that the hierarchical model of auditory processing may need to be revised to include an interaction between primary and functionally specialized areas depending on behavioral requirements.SIGNIFICANCE STATEMENT According to a purely hierarchical view, cortical auditory processing consists of a series of analysis stages from sensory (acoustic) processing in primary auditory cortex to specialized processing in higher-order areas. Posterior-dorsal cortical auditory areas, planum temporale (PT) in humans, are considered to be functionally specialized for spatial processing. However, this model is based mostly on passive listening studies. Our results provide compelling evidence that active behavior (sound localization) sharpens spatial selectivity in primary auditory cortex, whereas spatial tuning in functionally specialized areas (PT) is narrow but task-invariant. These findings suggest that the hierarchical view of cortical functional specialization needs to be extended: our data indicate that active behavior involves feedback projections from higher-order regions to primary auditory cortex.

Chronometry on Spike-LFP Responses Reveals the Functional Neural Circuitry of Early Auditory Cortex Underlying Sound Processing and Discrimination.

Animals and humans rapidly detect specific features of sounds, but the time courses of the underlying neural response for different stimulus categories is largely unknown. Furthermore, the intricate functional organization of auditory information processing pathways is poorly understood. Here, we computed neuronal response latencies from simultaneously recorded spike trains and local field potentials (LFPs) along the first two stages of cortical sound processing, primary auditory cortex (A1) and lateral belt (LB), of awake, behaving macaques. Two types of response latencies were measured for spike trains as well as LFPs: (1) onset latency, time-locked to onset of external auditory stimuli; and (2) selection latency, time taken from stimulus onset to a selective response to a specific stimulus category. Trial-by-trial LFP onset latencies predominantly reflecting synaptic input arrival typically preceded spike onset latencies, assumed to be representative of neuronal output indicating that both areas may receive input environmental signals and relay the information to the next stage. In A1, simple sounds, such as pure tones (PTs), yielded shorter spike onset latencies compared to complex sounds, such as monkey vocalizations ("Coos"). This trend was reversed in LB, indicating a hierarchical functional organization of auditory cortex in the macaque. LFP selection latencies in A1 were always shorter than those in LB for both PT and Coo reflecting the serial arrival of stimulus-specific information in these areas. Thus, chronometry on spike-LFP signals revealed some of the effective neural circuitry underlying complex sound discrimination.