Spatiotemporal patterns of locus coeruleus integrity predict cortical tau and cognition.

Autopsy studies indicated that the locus coeruleus (LC) accumulates hyperphosphorylated tau before allocortical regions in Alzheimer's disease. By combining in vivo longitudinal magnetic resonance imaging measures of LC integrity, tau positron emission tomography imaging and cognition with autopsy data and transcriptomic information, we examined whether LC changes precede allocortical tau deposition and whether specific genetic features underlie LC's selective vulnerability to tau. We found that LC integrity changes preceded medial temporal lobe tau accumulation, and together these processes were associated with lower cognitive performance. Common gene expression profiles between LC-medial temporal lobe-limbic regions map to biological functions in protein transport regulation. These findings advance our understanding of the spatiotemporal patterns of initial tau spreading from the LC and LC's selective vulnerability to Alzheimer's disease pathology. LC integrity measures can be a promising indicator for identifying the time window when individuals are at risk of disease progression and underscore the importance of interventions mitigating initial tau spread.

Association of Novelty-Related Locus Coeruleus Function With Entorhinal Tau Deposition and Memory Decline in Preclinical Alzheimer Disease.

BACKGROUND AND OBJECTIVES: The predictable Braak staging scheme suggests that cortical tau progression may be related to synaptically connected neurons. Animal and human neuroimaging studies demonstrated that changes in neuronal activity contribute to tau spreading. Whether similar mechanisms explain tau progression from the locus coeruleus (LC), a tiny noradrenergic brainstem nucleus involved in novelty, learning, and memory and among the earliest regions to accumulate tau, has not yet been established. We aimed to investigate whether novelty-related LC activity was associated with the accumulation of cortical tau and its implications for cognitive decline. METHODS: We combined functional MRI data of a novel vs repeated face-name learning paradigm, [18F]-FTP-PET, [11C]-PiB-PET, and longitudinal cognitive data from 92 well-characterized older individuals in the Harvard Aging Brain Study. We related novelty vs repetition LC activity to cortical tau deposition and to longitudinal decline in memory, executive function, and the Preclinical Alzheimer Disease Cognitive Composite (version 5; PACC5). Structural equation modeling was used to examine whether entorhinal cortical (EC) tau mediated the relationship between LC activity and cognitive decline and whether this depended on beta-amyloid deposition. RESULTS: The participants' average age at baseline was 69.67 ± 10.14 years. Fifty-one participants were female. Ninety-one participants were cognitively normal (CDR global = 0), and one participant had mild cognitive impairment (CDR global = 0.5) at baseline. Lower novelty-related LC activity was specifically related to greater tau deposition in the medial-lateral temporal cortex and steeper memory decline. LC activity during novelty vs repetition was not related to executive dysfunction or decline on the PACC5. The relationship between LC activity and memory decline was partially mediated by EC tau, particularly in individuals with elevated beta-amyloid deposition. DISCUSSION: Our results suggested that lower novelty-related LC activity is associated with the emergence of EC tau and that the downstream effects of this LC-EC pathway on memory decline also require the presence of elevated beta-amyloid. Longitudinal studies are required to investigate whether optimal LC activity has the potential to delay tau spread and memory decline, which may have implications for designing targeted interventions promoting resilience.

Hyperacusis is associated with smaller gray matter volumes in the supplementary motor area.

Hyperacusis is a disorder in loudness perception characterized by increased sensitivity to ordinary environmental sounds and associated with otologic conditions, including hearing loss and tinnitus (the phantom perception of sound) as well as neurologic and neuropsychiatric conditions. Hyperacusis is believed to arise centrally in the brain; however, the underlying causes are unknown. To gain insight into differences in brain morphology associated with hyperacusis, we undertook a retrospective case-control study comparing whole-brain gray matter morphology in participants with sensorineural hearing loss and tinnitus who either scored above or below the threshold for hyperacusis based on a standard questionnaire. We found that participants reporting hyperacusis had smaller gray matter volumes and cortical sheet thicknesses in the right supplementary motor area (SMA), independent of anxiety, depression, tinnitus burden, or sex. In fact, the right SMA volumes extracted from an independently defined volume of interest could accurately classify participants. Finally, in a subset of participants where functional data were also available, we found that individuals with hyperacusis showed increased sound-evoked responses in the right SMA compared to individuals without hyperacusis. Given the role of the SMA in initiating motion, these results suggest that in hyperacusis the SMA is involved in a motor response to sounds.

Effects of Physical Interventions on Subjective Tinnitus, a Systematic Review and Meta-Analysis.

Increasingly, patients suffering from subjective tinnitus seek help from physical therapists. Numerous randomised controlled trials (RCTs) have investigated the effect of physical interventions commonly used in physical therapy practice on subjective tinnitus. This systematic review and meta-analysis aimed to analyse the effects of physical interventions on tinnitus loudness, tinnitus annoyance, and scores on the Tinnitus Handicap Index (THI). Four databases were searched from inception up to March 2022. A total of 39 RCTs were included in the systematic review, and 23 studies were appropriate for meta-analyses. Risk of bias assessments were also performed. Interventions analysed in at least five studies were summarised, including transcutaneous electrical nerve stimulation (TENS), laser therapy, and acupuncture. Random-effects meta-analysis models were used, and effect sizes were expressed as Hedge's standardised mean differences (SMD) with 95%CI's. The quality of three-quarters of the studies was limited due to insufficient allocation concealment, lack of adequate blinding, and small sample sizes. Large, pooled effects sizes were found for acupuncture (SMD: 1.34; 95%CI: 0.79, 1.88) and TENS (SMD: 1.17; 95%CI: 0.48, 1.87) on THI as well as for acupuncture on tinnitus loudness (VAS Loudness (SMD: 0.84; 95%CI: 0.33, 1.36) and tinnitus annoyance (SMD: 1.18; 95%CI: 0.00, 2.35). There is some evidence that physical interventions (TENS and acupuncture, but not laser therapy) may be effective for tinnitus. However, the lack of high-quality studies and the risk of bias in many studies prohibits stronger conclusions.

State-of-the-art imaging of neuromodulatory subcortical systems in aging and Alzheimer's disease: Challenges and opportunities.

Primary prevention trials have shifted their focus to the earliest stages of Alzheimer's disease (AD). Autopsy data indicates that the neuromodulatory subcortical systems' (NSS) nuclei are specifically vulnerable to initial tau pathology, indicating that these nuclei hold great promise for early detection of AD in the context of the aging brain. The increasing availability of new imaging methods, ultra-high field scanners, new radioligands, and routine deep brain stimulation implants has led to a growing number of NSS neuroimaging studies on aging and neurodegeneration. Here, we review findings of current state-of-the-art imaging studies assessing the structure, function, and molecular changes of these nuclei during aging and AD. Furthermore, we identify the challenges associated with these imaging methods, important pathophysiologic gaps to fill for the AD NSS neuroimaging field, and provide future directions to improve our assessment, understanding, and clinical use of in vivo imaging of the NSS.

Automatic identification of tinnitus malingering based on overt and covert behavioral responses during psychoacoustic testing.

Tinnitus, or ringing in the ears, is a prevalent condition that imposes a substantial health and financial burden on the patient and to society. The diagnosis of tinnitus, like pain, relies on patient self-report, which can complicate the distinction between actual and fraudulent claims. Here, we combined tablet-based self-directed hearing assessments with neural network classifiers to automatically differentiate participants with tinnitus (N = 24) from a malingering cohort, who were instructed to feign an imagined tinnitus percept (N = 28). We identified clear differences between the groups, both in their overt reporting of tinnitus features, but also covert differences in their fingertip movement trajectories on the tablet surface as they performed the reporting assay. Using only 10 min of data, we achieved 81% accuracy classifying patients and malingerers (ROC AUC = 0.88) with leave-one-out cross validation. Quantitative, automated measurements of tinnitus salience could improve clinical outcome assays and more accurately determine tinnitus incidence.

Cerebellar Gray Matter Volume in Tinnitus.

Tinnitus is the perception of sound without an external source. The flocculus (FL) and paraflocculus (PFL), which are small lobules of the cerebellum, have recently been implicated in its pathophysiology. In a previous study, the volume of the (P)FL-complex correlated with tinnitus severity in patients that had undergone cerebellopontine angle (CPA) tumor removal. In this study, the relation between tinnitus and gray matter volume (GMV) of the (P)FL-complex, GMV of the other cerebellar lobules and GMV of the cerebellar nuclei is investigated in otherwise healthy participants. Data was processed using the SUIT toolbox, which is dedicated to analysis of imaging data of the human cerebellum. GMV of all cerebellar lobules and nuclei were similar between tinnitus and non-tinnitus participants. Moreover, no relation was present between tinnitus severity, as measured by the Tinnitus Handicap Inventory, and (P)FL-complex GMV, tonsil GMV, or total cerebellar cortical GMV. These results suggest that in otherwise healthy participants, in contrast to participants after CPA tumor removal, no relation between the GMV of neither the (P)FL-complex nor other cerebellar lobules and tinnitus presence and severity exists. These findings indicate that a relation only exists when the (P)FL-complex is damaged, for instance by a CPA tumor. Alternatively, it is possible that differences in (P)FL-complex GMVs are too small to detect with a voxel-based morphometry study. Therefore, the role of the (P)FL-complex in tinnitus remains to be further studied.

The thalamus and tinnitus: Bridging the gap between animal data and findings in humans.

The neuronal mechanisms underlying tinnitus are yet to be revealed. Tinnitus, an auditory phantom sensation, used to be approached as a purely auditory domain symptom. More recently, the modulatory impact of non-auditory brain regions on the percept and burden of tinnitus are explored. The thalamus is uniquely situated to facilitate the communication between auditory and non-auditory subcortical and cortical structures. Traditionally, animal models of tinnitus have focussed on subcortical auditory structures, and research with human participants has been concerned with cortical activity in auditory and non-auditory areas. Recently, both research fields have investigated the connectivity between subcortical and cortical regions and between auditory and non-auditory areas. We show that even though the different fields employ different methods to investigate the activity and connectivity of brain areas, there is consistency in the results on tinnitus between these different approaches. This consistency between human and animals research is observed for tinnitus with peripherally instigated hearing damage, and for results obtained with salicylate and noise-induced tinnitus. The thalamus integrates input from limbic and prefrontal areas and modulates auditory activity via its connections to both subcortical and cortical auditory areas. Reported altered activity and connectivity of the auditory, prefrontal, and limbic regions suggest a more systemic approach is necessary to understand the origins and impact of tinnitus.

Macrostructural Changes of the Acoustic Radiation in Humans with Hearing Loss and Tinnitus Revealed with Fixel-Based Analysis.

Age-related hearing loss is the most prevalent sensory impairment in the older adult population and is related to noise-induced damage or age-related deterioration of the peripheral auditory system. Hearing loss may affect the central auditory pathway in the brain, which is a continuation of the peripheral auditory system located in the ear. A debilitating symptom that frequently co-occurs with hearing loss is tinnitus. Strikingly, investigations into the impact of acquired hearing loss, with and without tinnitus, on the human central auditory pathway are sparse. This study used diffusion-weighted imaging (DWI) to investigate changes in the largest central auditory tract, the acoustic radiation, related to hearing loss and tinnitus. Participants with hearing loss, with and without tinnitus, and a control group were included. Both conventional diffusion tensor analysis and higher-order fixel-based analysis were applied. The fixel-based analysis was used as a novel framework providing insight into the axonal density and macrostructural morphologic changes of the acoustic radiation in hearing loss and tinnitus. The results show tinnitus-related atrophy of the left acoustic radiation near the medial geniculate body. This finding may reflect a decrease in myelination of the auditory pathway, instigated by more profound peripheral deafferentation or reflecting a preexisting marker of tinnitus vulnerability. Furthermore, age was negatively correlated with the axonal density in the bilateral acoustic radiation. This loss of fiber density with age may contribute to poorer speech understanding observed in older adults.SIGNIFICANCE STATEMENT Age-related hearing loss is the most prevalent sensory impairment in the older adult population. Older individuals are subject to the cumulative effects of aging and noise exposure on the auditory system. A debilitating symptom that frequently co-occurs with hearing loss is tinnitus: the perception of a phantom sound. In this large DWI-study, we provide evidence that in hearing loss, the additional presence of tinnitus is related to degradation of the acoustic radiation. Additionally, older age was related to axonal loss in the acoustic radiation. It appears that older adults have the aggravating circumstances of age, hearing loss, and tinnitus on central auditory processing, which may partly be because of the observed deterioration of the acoustic radiation with age.

Gray matter declines with age and hearing loss, but is partially maintained in tinnitus.

The impact of age-related hearing loss extends beyond the auditory pathway and impacts brain areas related to cognitive impairment and even dementia. The presence of tinnitus, a sensation of sound that frequently co-occurs with hearing loss, is additionally linked to cognitive decline. Interestingly, structural neuroimaging studies have reported that hearing loss may precede or modulate the onset of cognitive impairment. In this study, we aimed to disentangle the effects of age, hearing loss, and tinnitus on gray matter structure. In total, 39 participants with hearing loss and tinnitus, 21 with hearing loss but without tinnitus, and 39 controls were included in this voxel- and surface-based morphometry MRI study. Whole brain volume and surface thickness measures were compared between the groups. Age-related gray matter volume decline was observed in all groups. Several brain areas showed smaller gray matter volume and cortical surface thickness in hearing loss without tinnitus, relative to controls. This reduction was observed both within and outside of the auditory pathway. Interestingly, these reductions were not observed in participants with tinnitus, who had similar hearing loss and were of similar age. Since we have tools to improve hearing loss, hearing screening may aid in the battle against cognitive decline.

Cortical Tonotopic Map Changes in Humans Are Larger in Hearing Loss Than in Additional Tinnitus.

Neural plasticity due to hearing loss results in tonotopic map changes. Several studies have suggested a relation between hearing loss-induced tonotopic reorganization and tinnitus. This large fMRI study on humans was intended to clarify the relations between hearing loss, tinnitus, and tonotopic reorganization. To determine the differential effect of hearing loss and tinnitus, both male and female participants with bilateral high-frequency hearing loss, with and without tinnitus, and a control group were included. In a total of 90 participants, bilateral cortical responses to sound stimulation were measured with loudness-matched pure-tone stimuli (0.25-8 kHz). In the bilateral auditory cortices, the high-frequency sound-evoked activation level was higher in both hearing-impaired participant groups, compared with the control group. This was most prominent in the hearing loss group without tinnitus. Similarly, the tonotopic maps for the hearing loss without tinnitus group were significantly different from the controls, whereas the maps of those with tinnitus were not. These results show that higher response amplitudes and map reorganization are a characteristic of hearing loss, not of tinnitus. Both tonotopic maps and response amplitudes of tinnitus participants appear intermediate to the controls and hearing loss without tinnitus group. This observation suggests a connection between tinnitus and an incomplete form of central compensation to hearing loss, rather than excessive adaptation. One implication of this may be that treatments for tinnitus shift their focus toward enhancing the cortical plasticity, instead of reversing it.SIGNIFICANCE STATEMENT Tinnitus, a common and potentially devastating condition, is the presence of a "phantom" sound that often accompanies hearing loss. Hearing loss is known to induce plastic changes in cortical and subcortical areas. Although plasticity is a valuable trait that allows the human brain to rewire and recover from injury and sensory deprivation, it can lead to tinnitus as an unwanted side effect. In this large fMRI study, we provide evidence that tinnitus is related to a more conservative form of reorganization than in hearing loss without tinnitus. This result contrasts with the previous notion that tinnitus is related to excessive reorganization. As a consequence, treatments for tinnitus may need to enhance the cortical plasticity, rather than reverse it.

Profiling intermittent tinnitus: a retrospective review.

Objective: We conducted a retrospective review of medical records of tinnitus patients at a tertiary ENT clinic in Groningen, Netherlands. Our goal was to identify factors that differentiated the intermittent subgroup from the larger continuous group with chronic tinnitus. Design: Tinnitus-related factors such as hearing loss, emotional aspects, and demographics were used to advance our understanding of the subgroups. We analysed the data using descriptive statistics and binomial logistic regression, supplemented by random forests classification. Study sample: Patients presenting with tinnitus visiting the tinnitus clinic. We examined 1575 medical intake records obtained at a tertiary ENT hospital. Results: Duration, total Tinnitus Handicap Inventory (THI), and THI Functional subscale scores differed significantly between the two groups. Increasing age and higher THI Emotional subscale scores were associated with an increased likelihood of intermittent tinnitus. Increases in duration, depressive scores and THI Functional and Catastrophic subscale scores, decreased the likelihood of intermittent tinnitus. Conclusions: Results from this study dissociate the factors affecting those with intermittent and those with continuous tinnitus and point to potentially different mechanisms underlying the two conditions.

Functional (psychogenic) movement disorders associated with normal scores in psychological questionnaires: A case control study.

OBJECTIVE: Functional movement disorders (FMDs) fall within the broader category called functional neurological symptom disorder (FNSD). New DSM-5 criteria for FNSD no longer require the presence of a 'psychological conflict' suggesting that some patients with FMD may not have obvious psychological comorbidity. We studied patients with FMD in comparison to patients with a neurological movement disorder (MD) and healthy controls (HC) to identify whether there is a subgroup of patients with FMD who have normal psychological test scores. METHODS: We assessed self-rated measures of depression/anxiety (SCL-90), dissociation and personality disorder (PDQ-4) in patients attending neurological clinics and healthy controls. The proportion of patients scoring within normal ranges was determined, and the levels of somatic and psychological symptoms were compared between the three groups. RESULTS: Among the FMD group, 39% (20/51) scored within the normal range for all measures compared to 38% (13/34) of MD subjects and 89% (47/53) of healthy controls. There were no differences in overall scores in the SCL-90 and PDQ-4 between FMD and MD patients. FMD patients also did not differ from controls on a self-rated measure of personality pathology. CONCLUSION: Our data show that a substantial proportion of patients with FMD score within the normal range in psychological questionnaires, lending some support to the new DSM-5 criteria.