A pilot dose-finding study of Terazosin in humans.

Background: Parkinson's disease (PD) is a prevalent neurodegenerative disorder where progressive neuron loss is driven by impaired brain bioenergetics, particularly mitochondrial dysfunction and disrupted cellular respiration. Terazosin (TZ), an α-1 adrenergic receptor antagonist with a known efficacy in treating benign prostatic hypertrophy and hypertension, has shown potential in addressing energy metabolism deficits associated with PD due to its action on phosphoglycerate kinase 1 (PGK1). This study aimed to investigate the safety, tolerability, bioenergetic target engagement, and optimal dose of TZ in neurologically healthy subjects. Methods: Eighteen healthy men and women (60 - 85 years old) were stratified into two cohorts based on maximum TZ dosages (5 mg and 10 mg daily). Methods included plasma and cerebrospinal fluid TZ concentration measurements, whole blood ATP levels, 31 Phosphorous magnetic resonance spectroscopy for brain ATP levels, 18 F-FDG PET imaging for cerebral metabolic activity, and plasma metabolomics. Results: Our results indicated that a 5 mg/day dose of TZ significantly increased whole blood ATP levels and reduced global cerebral 18 F-FDG PET uptake without significant side effects or orthostatic hypotension. These effects were consistent across sexes. Higher doses did not result in additional benefits and showed a potential biphasic dose-response. Conclusions: TZ at a dosage of 5 mg/day engages its metabolic targets effectively in both sexes without inducing significant adverse effects and provides a promising therapeutic avenue for mitigating energetic deficiencies. Further investigation via clinical trials to validate TZ's efficacy and safety in neurodegenerative (i.e., PD) contexts is warranted.

Temporally organized representations of reward and risk in the human brain.

The value and uncertainty associated with choice alternatives constitute critical features relevant for decisions. However, the manner in which reward and risk representations are temporally organized in the brain remains elusive. Here we leverage the spatiotemporal precision of intracranial electroencephalography, along with a simple card game designed to elicit the unfolding computation of a set of reward and risk variables, to uncover this temporal organization. Reward outcome representations across wide-spread regions follow a sequential order along the anteroposterior axis of the brain. In contrast, expected value can be decoded from multiple regions at the same time, and error signals in both reward and risk domains reflect a mixture of sequential and parallel encoding. We further highlight the role of the anterior insula in generalizing between reward prediction error and risk prediction error codes. Together our results emphasize the importance of neural dynamics for understanding value-based decisions under uncertainty.

What is the role of the hippocampus and parahippocampal gyrus in the persistence of tinnitus?

The hippocampus and parahippocampal gyrus have been implicated as part of a tinnitus network by a number of studies. These structures are usually considered in the context of a "limbic system," a concept typically invoked to explain the emotional response to tinnitus. Despite this common framing, it is not apparent from current literature that this is necessarily the main functional role of these structures in persistent tinnitus. Here, we highlight a different role that encompasses their most commonly implicated functional position within the brain-that is, as a memory system. We consider tinnitus as an auditory object that is held in memory, which may be made persistent by associated activity from the hippocampus and parahippocampal gyrus. Evidence from animal and human studies implicating these structures in tinnitus is reviewed and used as an anchor for this hypothesis. We highlight the potential for the hippocampus/parahippocampal gyrus to facilitate maintenance of the memory of the tinnitus percept via communication with auditory cortex, rather than (or in addition to) mediating emotional responses to this percept.

Effects of transcranial magnetic stimulation on the human brain recorded with intracranial electrocorticography.

Transcranial magnetic stimulation (TMS) is increasingly used as a noninvasive technique for neuromodulation in research and clinical applications, yet its mechanisms are not well understood. Here, we present the neurophysiological effects of TMS using intracranial electrocorticography (iEEG) in neurosurgical patients. We first evaluated safety in a gel-based phantom. We then performed TMS-iEEG in 22 neurosurgical participants with no adverse events. We next evaluated intracranial responses to single pulses of TMS to the dorsolateral prefrontal cortex (dlPFC) (N = 10, 1414 electrodes). We demonstrate that TMS is capable of inducing evoked potentials both locally within the dlPFC and in downstream regions functionally connected to the dlPFC, including the anterior cingulate and insular cortex. These downstream effects were not observed when stimulating other distant brain regions. Intracranial dlPFC electrical stimulation had similar timing and downstream effects as TMS. These findings support the safety and promise of TMS-iEEG in humans to examine local and network-level effects of TMS with higher spatiotemporal resolution than currently available methods.

Mimicry in misophonia: A large-scale survey of prevalence and relationship with trigger sounds.

BACKGROUND: Misophonia is often referred to as a disorder that is characterized by excessive negative emotional responses, including anger and anxiety, to "trigger sounds" which are typically day-to-day sounds, such as those generated from people eating, chewing, and breathing. Misophonia (literally "hatred of sounds") has commonly been understood within an auditory processing framework where sounds cause distress due to aberrant processing in the auditory and emotional systems of the brain. However, a recent proposal suggests that it is the perceived action (e.g., mouth movement in eating/chewing sounds as triggers) of the trigger person, and not the sounds per se, that drives the distress in misophonia. Since observation or listening to sounds of actions of others are known to prompt mimicry in perceivers, we hypothesized that mimicking the action of the trigger person may be prevalent in misophonia. Apart from a few case studies and anecdotal information, a relation between mimicking and misophonia has not been systematically evaluated. METHOD: In this work, we addressed this limitation by collecting data on misophonia symptoms and mimicry behavior using online questionnaires from 676 participants. RESULTS: Analysis of these data shows that (i) more than 45% of individuals with misophonia reported mimicry, indicating its wide prevalence, (ii) the tendency to mimic varies in direct proportion to misophonia severity, (iii) compared to other human and environmental sounds, trigger sounds of eating and chewing are more likely to trigger mimicking, and (iv) the act of mimicking provides some degree of relief from distress to people with misophonia. CONCLUSION: This study shows prevalence of mimicry and its relation to misophonia severity and trigger types. The theoretical framework of misophonia needs to incorporate the phenomenon of mimicry and its effect on management of misophonia distress.

Spectral Grouping of Electrically Encoded Sound Predicts Speech-in-Noise Performance in Cochlear Implantees.

OBJECTIVES: Cochlear implant (CI) users exhibit large variability in understanding speech in noise. Past work in CI users found that spectral and temporal resolution correlates with speech-in-noise ability, but a large portion of variance remains unexplained. Recent work on normal-hearing listeners showed that the ability to group temporally and spectrally coherent tones in a complex auditory scene predicts speech-in-noise ability independently of the audiogram, highlighting a central mechanism for auditory scene analysis that contributes to speech-in-noise. The current study examined whether the auditory grouping ability also contributes to speech-in-noise understanding in CI users. DESIGN: Forty-seven post-lingually deafened CI users were tested with psychophysical measures of spectral and temporal resolution, a stochastic figure-ground task that depends on the detection of a figure by grouping multiple fixed frequency elements against a random background, and a sentence-in-noise measure. Multiple linear regression was used to predict sentence-in-noise performance from the other tasks. RESULTS: No co-linearity was found between any predictor variables. All three predictors (spectral and temporal resolution plus the figure-ground task) exhibited significant contribution in the multiple linear regression model, indicating that the auditory grouping ability in a complex auditory scene explains a further proportion of variance in CI users' speech-in-noise performance that was not explained by spectral and temporal resolution. CONCLUSION: Measures of cross-frequency grouping reflect an auditory cognitive mechanism that determines speech-in-noise understanding independently of cochlear function. Such measures are easily implemented clinically as predictors of CI success and suggest potential strategies for rehabilitation based on training with non-speech stimuli.

Immediate neural impact and incomplete compensation after semantic hub disconnection.

The human brain extracts meaning using an extensive neural system for semantic knowledge. Whether broadly distributed systems depend on or can compensate after losing a highly interconnected hub is controversial. We report intracranial recordings from two patients during a speech prediction task, obtained minutes before and after neurosurgical treatment requiring disconnection of the left anterior temporal lobe (ATL), a candidate semantic knowledge hub. Informed by modern diaschisis and predictive coding frameworks, we tested hypotheses ranging from solely neural network disruption to complete compensation by the indirectly affected language-related and speech-processing sites. Immediately after ATL disconnection, we observed neurophysiological alterations in the recorded frontal and auditory sites, providing direct evidence for the importance of the ATL as a semantic hub. We also obtained evidence for rapid, albeit incomplete, attempts at neural network compensation, with neural impact largely in the forms stipulated by the predictive coding framework, in specificity, and the modern diaschisis framework, more generally. The overall results validate these frameworks and reveal an immediate impact and capability of the human brain to adjust after losing a brain hub.

Effect of Post-COVID-19 on Brain Volume and Glucose Metabolism: Influence of Time Since Infection and Fatigue Status.

Post-COVID-19 syndrome (PCS) fatigue is typically most severe <6 months post-infection. Combining magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging with the glucose analog [18F]-Fluorodeoxyglucose (FDG) provides a comprehensive overview of the effects of PCS on regional brain volumes and metabolism, respectively. The primary purpose of this exploratory study was to investigate differences in MRI/PET outcomes between people < 6 months (N = 18, 11 female) and > 6 months (N = 15, 6 female) after COVID-19. The secondary purpose was to assess if any differences in MRI/PET outcomes were associated with fatigue symptoms. Subjects > 6 months showed smaller volumes in the putamen, pallidum, and thalamus compared to subjects < 6 months. In subjects > 6 months, fatigued subjects had smaller volumes in frontal areas compared to non-fatigued subjects. Moreover, worse fatigue was associated with smaller volumes in several frontal areas in subjects > 6 months. The results revealed no brain metabolism differences between subjects > 6 and < 6 months. However, both groups exhibited both regional hypo- and hypermetabolism compared to a normative database. These results suggest that PCS may alter regional brain volumes but not metabolism in people > 6 months, particularly those experiencing fatigue symptoms.

Distribution of multiunit pitch responses recorded intracranially from human auditory cortex.

The perception of pitch is a fundamental percept, which is mediated by the auditory system, requiring the abstraction of stimulus properties related to the spectro-temporal structure of sound. Despite its importance, there is still debate as to the precise areas responsible for its encoding, which may be due to species differences or differences in the recording measures and choices of stimuli used in previous studies. Moreover, it was unknown whether the human brain contains pitch neurons and how distributed such neurons might be. Here, we present the first study to measure multiunit neural activity in response to pitch stimuli in the auditory cortex of intracranially implanted humans. The stimulus sets were regular-interval noise with a pitch strength that is related to the temporal regularity and a pitch value determined by the repetition rate and harmonic complexes. Specifically, we demonstrate reliable responses to these different pitch-inducing paradigms that are distributed throughout Heschl's gyrus, rather than being localized to a particular region, and this finding was evident regardless of the stimulus presented. These data provide a bridge across animal and human studies and aid our understanding of the processing of a critical percept associated with acoustic stimuli.

Neural Correlates of Individual Differences in Speech-in-Noise Performance in a Large Cohort of Cochlear Implant Users.

OBJECTIVES: Understanding speech-in-noise (SiN) is a complex task that recruits multiple cortical subsystems. Individuals vary in their ability to understand SiN. This cannot be explained by simple peripheral hearing profiles, but recent work by our group ( Kim et al. 2021 , Neuroimage ) highlighted central neural factors underlying the variance in SiN ability in normal hearing (NH) subjects. The present study examined neural predictors of SiN ability in a large cohort of cochlear-implant (CI) users. DESIGN: We recorded electroencephalography in 114 postlingually deafened CI users while they completed the California consonant test: a word-in-noise task. In many subjects, data were also collected on two other commonly used clinical measures of speech perception: a word-in-quiet task (consonant-nucleus-consonant) word and a sentence-in-noise task (AzBio sentences). Neural activity was assessed at a vertex electrode (Cz), which could help maximize eventual generalizability to clinical situations. The N1-P2 complex of event-related potentials (ERPs) at this location were included in multiple linear regression analyses, along with several other demographic and hearing factors as predictors of SiN performance. RESULTS: In general, there was a good agreement between the scores on the three speech perception tasks. ERP amplitudes did not predict AzBio performance, which was predicted by the duration of device use, low-frequency hearing thresholds, and age. However, ERP amplitudes were strong predictors for performance for both word recognition tasks: the California consonant test (which was conducted simultaneously with electroencephalography recording) and the consonant-nucleus-consonant (conducted offline). These correlations held even after accounting for known predictors of performance including residual low-frequency hearing thresholds. In CI-users, better performance was predicted by an increased cortical response to the target word, in contrast to previous reports in normal-hearing subjects in whom speech perception ability was accounted for by the ability to suppress noise. CONCLUSIONS: These data indicate a neurophysiological correlate of SiN performance, thereby revealing a richer profile of an individual's hearing performance than shown by psychoacoustic measures alone. These results also highlight important differences between sentence and word recognition measures of performance and suggest that individual differences in these measures may be underwritten by different mechanisms. Finally, the contrast with prior reports of NH listeners in the same task suggests CI-users performance may be explained by a different weighting of neural processes than NH listeners.

Temporally organized representations of reward and risk in the human brain.

The value and uncertainty associated with choice alternatives constitute critical features along which decisions are made. While the neural substrates supporting reward and risk processing have been investigated, the temporal organization by which these computations are encoded remains elusive. Here we leverage the high spatiotemporal precision of intracranial electroencephalography (iEEG) to uncover how representations of decision-related computations unfold in time. We present evidence of locally distributed representations of reward and risk variables that are temporally organized across multiple regions of interest. Reward outcome representations across wide-spread regions follow a temporally cascading order along the anteroposterior axis of the brain. In contrast, expected value can be decoded from multiple regions at the same time, and error signals in both reward and risk domains reflect a mixture of sequential and parallel encoding. We highlight the role of the anterior insula in generalizing between reward prediction error (RePE) and risk prediction error (RiPE), within which the encoding of RePE in the distributed iEEG signal predicts RiPE. Together our results emphasize the utility of uncovering temporal dynamics in the human brain for understanding how computational processes critical for value-based decisions under uncertainty unfold.

Differences in Inhibitory Control and Resting Brain Metabolism between Older Chronic Users of Tetrahydrocannabinol (THC) or Cannabidiol (CBD)-A Pilot Study.

Δ9-Tetrahydrocannabinol is the main psychoactive component of cannabis and cannabidiol is purportedly responsible for many of the medicinal benefits. The effects of Δ9-tetrahydrocannabinol and cannabidiol in younger populations have been well studied; however, motor function, cognitive function, and cerebral glucose metabolism in older adults have not been extensively researched. The purpose of this study was to assess differences in cognitive function, motor function, and cerebral glucose metabolism (assessed via [18F]-fluorodeoxyglucose positron emission tomography) in older adults chronically using Δ9-tetrahydrocannabinol, cannabidiol, and non-using controls. Eight Δ9-tetrahydrocannabinol users (59.3 ± 5.7 years), five cannabidiol users (54.6 ± 2.1 years), and 16 non-users (58.2 ± 16.9 years) participated. Subjects underwent resting scans and performed cognitive testing (reaction time, Flanker Inhibitory Control and Attention Test), motor testing (hand/arm function, gait), and balance testing. Δ9-tetrahydrocannabinol users performed worse than both cannabidiol users and non-users on the Flanker Test but were similar on all other cognitive and motor tasks. Δ9-tetrahydrocannabinol users also had lower global metabolism and relative hypermetabolism in the bilateral amygdala, cerebellum, and brainstem. Chronic use of Δ9-tetrahydrocannabinol in older adults might negatively influence inhibitory control and alter brain activity. Future longitudinal studies with larger sample sizes investigating multiple Δ9-tetrahydrocannabinol:cannabidiol ratios on functional outcomes and cerebral glucose metabolism in older adults are necessary.

Validation of the Iowa Test of Consonant Perception.

Speech perception (especially in background noise) is a critical problem for hearing-impaired listeners and an important issue for cognitive hearing science. Despite a plethora of standardized measures, few single-word closed-set tests uniformly sample the most frequently used phonemes and use response choices that equally sample phonetic features like place and voicing. The Iowa Test of Consonant Perception (ITCP) attempts to solve this. It is a proportionally balanced phonemic word recognition task designed to assess perception of the initial consonant of monosyllabic consonant-vowel-consonant (CVC) words. The ITCP consists of 120 sampled CVC words. Words were recorded from four different talkers (two female) and uniformly sampled from all four quadrants of the vowel space to control for coarticulation. Response choices on each trial are balanced to equate difficulty and sample a single phonetic feature. This study evaluated the psychometric properties of ITCP by examining reliability (test-retest) and validity in a sample of online normal-hearing participants. Ninety-eight participants completed two sessions of the ITCP along with standardized tests of words and sentence in noise (CNC words and AzBio sentences). The ITCP showed good test-retest reliability and convergent validity with two popular tests presented in noise. All the materials to use the ITCP or to construct your own version of the ITCP are freely available [Geller, McMurray, Holmes, and Choi (2020). https://osf.io/hycdu/].

The Motor Basis for Misophonia.

Misophonia is a common disorder characterized by the experience of strong negative emotions of anger and anxiety in response to certain everyday sounds, such as those generated by other people eating, drinking, and breathing. The commonplace nature of these "trigger" sounds makes misophonia a devastating disorder for sufferers and their families. How such innocuous sounds trigger this response is unknown. Since most trigger sounds are generated by orofacial movements (e.g., chewing) in others, we hypothesized that the mirror neuron system related to orofacial movements could underlie misophonia. We analyzed resting state fMRI (rs-fMRI) connectivity (N = 33, 16 females) and sound-evoked fMRI responses (N = 42, 29 females) in misophonia sufferers and controls. We demonstrate that, compared with controls, the misophonia group show no difference in auditory cortex responses to trigger sounds, but do show: (1) stronger rs-fMRI connectivity between both auditory and visual cortex and the ventral premotor cortex responsible for orofacial movements; (2) stronger functional connectivity between the auditory cortex and orofacial motor area during sound perception in general; and (3) stronger activation of the orofacial motor area, specifically, in response to trigger sounds. Our results support a model of misophonia based on "hyper-mirroring" of the orofacial actions of others with sounds being the "medium" via which action of others is excessively mirrored. Misophonia is therefore not an abreaction to sounds, per se, but a manifestation of activity in parts of the motor system involved in producing those sounds. This new framework to understand misophonia can explain behavioral and emotional responses and has important consequences for devising effective therapies.SIGNIFICANCE STATEMENT Conventionally, misophonia, literally "hatred of sounds" has been considered as a disorder of sound emotion processing, in which "simple" eating and chewing sounds produced by others cause negative emotional responses. Our data provide an alternative but complementary perspective on misophonia that emphasizes the action of the trigger-person rather than the sounds which are a byproduct of that action. Sounds, in this new perspective, are only a "medium" via which action of the triggering-person is mirrored onto the listener. This change in perspective has important consequences for devising therapies and treatment methods for misophonia. It suggests that, instead of focusing on sounds, which many existing therapies do, effective therapies should target the brain representation of movement.

Pre- and post-target cortical processes predict speech-in-noise performance.

Understanding speech in noise (SiN) is a complex task that recruits multiple cortical subsystems. There is a variance in individuals' ability to understand SiN that cannot be explained by simple hearing profiles, which suggests that central factors may underlie the variance in SiN ability. Here, we elucidated a few cortical functions involved during a SiN task and their contributions to individual variance using both within- and across-subject approaches. Through our within-subject analysis of source-localized electroencephalography, we investigated how acoustic signal-to-noise ratio (SNR) alters cortical evoked responses to a target word across the speech recognition areas, finding stronger responses in left supramarginal gyrus (SMG, BA40 the dorsal lexicon area) with quieter noise. Through an individual differences approach, we found that listeners show different neural sensitivity to the background noise and target speech, reflected in the amplitude ratio of earlier auditory-cortical responses to speech and noise, named as an internal SNR. Listeners with better internal SNR showed better SiN performance. Further, we found that the post-speech time SMG activity explains a further amount of variance in SiN performance that is not accounted for by internal SNR. This result demonstrates that at least two cortical processes contribute to SiN performance independently: pre-target time processing to attenuate neural representation of background noise and post-target time processing to extract information from speech sounds.

Oscillatory correlates of auditory working memory examined with human electrocorticography.

This work examines how sounds are held in auditory working memory (AWM) in humans by examining oscillatory local field potentials (LFPs) in candidate brain regions. Previous fMRI studies by our group demonstrated blood oxygenation level-dependent (BOLD) response increases during maintenance in auditory cortex, inferior frontal cortex and the hippocampus using a paradigm with a delay period greater than 10s. The relationship between such BOLD changes and ensemble activity in different frequency bands is complex, and the long delay period raised the possibility that long-term memory mechanisms were engaged. Here we assessed LFPs in different frequency bands in six subjects with recordings from all candidate brain regions using a paradigm with a short delay period of 3 s. Sustained delay activity was demonstrated in all areas, with different patterns in the different areas. Enhancement in low frequency (delta) power and suppression across higher frequencies (beta/gamma) were demonstrated in primary auditory cortex in medial Heschl's gyrus (HG) whilst non-primary cortex showed patterns of enhancement and suppression that altered at different levels of the auditory hierarchy from lateral HG to superior- and middle-temporal gyrus. Inferior frontal cortex showed increasing suppression with increasing frequency. The hippocampus and parahippocampal gyrus showed low frequency increases and high frequency decreases in oscillatory activity. This work demonstrates sustained activity patterns during AWM maintenance, with prominent low-frequency increases in medial temporal lobe regions.

Exposing Pathological Sensory Predictions in Tinnitus Using Auditory Intensity Deviant Evoked Responses.

We tested the popular, unproven theory that tinnitus is caused by resetting of auditory predictions toward a persistent low-intensity sound. Electroencephalographic mismatch negativity responses, which quantify the violation of sensory predictions, to unattended tinnitus-like sounds were greater in response to upward than downward intensity deviants in 26 unselected chronic tinnitus subjects with normal to severely impaired hearing, and in 15 acute tinnitus subjects, but not in 26 hearing and age-matched controls (p < 0.001, receiver operator characteristic, area under the curve, 0.77), or in 20 healthy and hearing-impaired controls presented with simulated tinnitus. The findings support a prediction resetting model of tinnitus generation, and may form the basis of a convenient tinnitus biomarker, which we name Intensity Mismatch Asymmetry, which is usable across species, is quick and tolerable, and requires no training.SIGNIFICANCE STATEMENT In current models, perception is based around the generation of internal predictions of the environment, which are tested and updated using evidence from the senses. Here, we test the theory that auditory phantom perception (tinnitus) occurs when a default auditory prediction is formed to explain spontaneous activity in the subcortical pathway, rather than ignoring it as noise. We find that chronic tinnitus patients show an abnormal pattern of evoked responses to unexpectedly loud and quiet sounds that both supports this hypothesis and provides fairly accurate classification of tinnitus status at the individual subject level. This approach to objectively demonstrating the predictions underlying pathological perceptual states may also have a much wider utility, for instance, in chronic pain.