David S. Wack

The functional neuroanatomy of tinnitus Evidence for limbic system links and neural plasticity

We used PET to map brain regions responding to changes in tinnitus loudness in four patients who could alter tinnitus loudness by performing voluntary oral facial movements (OFMs). Cerebral blood flow was measured in four patients and six controls at rest, during the OFM, and during stimulation with pure tones. OFM-induced loudness changes affected the auditory cortex contralateral to the ear in which tinnitus was perceived, whereas unilateral cochlear stimulation caused bilateral effects, suggesting a retrocochlear origin for their tinnitus. Patients, compared with controls, showed evidence for more widespread activation by the tones and aberrant links between the limbic and auditory systems. These abnormal patterns provide evidence for cortical plasticity that may account for tinnitus and associated symptoms. Although audiologic symptoms and examinations of these patients were typical, the unusual ability to modulate tinnitus loudness with an OFM suggests some caution may be warranted in generalizing these findings.

The functional anatomy of gaze-evoked tinnitus and sustained lateral gaze

Objective: To identify neural sites associated with gaze-evoked tinnitus (GET), an unusual condition that may follow cerebellar–pontine angle surgery. Methods: The authors examined eight patients with GET and used PET to map the neural sites activated by lateral gaze in them and seven age- and sex-matched control subjects. Results: In patients with GET, tinnitus loudness and pitch increased with lateral gaze and, to a lesser extent, up and down gaze. Evidence for neural activity related to GET was seen in the auditory lateral pontine tegmentum or auditory cortex. GET-associated nystagmus appears to activate the cuneus and cerebellar vermis. These sites were found in addition to an extensive network that included frontal eye fields and other sites in frontal, parietal, and temporal cortex that were activated by lateral gaze in seven control subjects and the patients. The unilateral deafness in patients with GET was associated with expansion of auditory cortical areas responsive to tones delivered to the good ear. In addition to GET, unilateral deafness, end-gaze nystagmus, and facial nerve dysfunction were common. Conclusions: Patients with GET have plastic changes in multiple neural systems that allow neural activity associated with eye movement, including those associated with the neural integrator, to stimulate the auditory system. Anomalous auditory activation is enhanced by the failure of cross-modal inhibition to suppress auditory cortical activity. The time course for the development of GET suggests that it may be due to multiple mechanisms.

Brain imaging of the effects of lidocaine on tinnitus

Using a single-blind placebo-controlled design, we mapped lidocaine related changes in neural activity, measured by regional cerebral blood flow (rCBF) with (15)O-H(2)O positron emission tomography. Intravenous lidocaine produced both increases and decreases in the loudness of tinnitus. The change in tinnitus loudness was associated with a statistically significant change in neural activity in the right temporal lobe in auditory association cortex. Decreases in tinnitus loudness resulted in larger changes in rCBF than increases. The unilateral activation pattern associated with tinnitus, in contrast with the bilateral activation produced by a real sound, suggests that tinnitus originates in the central auditory system rather than the cochlea. In addition, generalized lidocaine effects were found in the basal ganglia, thalamus, and a region spanning the Rolandic fissure.

Sex differences in brain regions activated by grammatical and reading tasks

DO the brains of men and women show similar patterns of functional organization for language, or are men more strongly lateralized? We used PET to measure cerebral blood flow (CBF) as men and women read real and nonce verbs, and produced past tense forms. While the overall patterns of reaction time, error, and brain activation were similar, there were also significant sex-related differences in CBF patterns. During the past tense generation tasks, men showed left-lateralized activation while women recruited bilateral perisylvian cortex, confirming differences in functional laterality. During all tasks, women showed higher activation in occipital and/or cerebellar regions, suggesting differences in basic reading strategies. We conclude that sex differences in functional cortical organization exist in the absence of significant behavioral differences.

Neural correlates of tinnitus duration and Distress: A positron emission tomography study

Cerebral 18F‐deoxyglucose positron emission tomography (FDG‐PET) has shown altered auditory pathway activity in tinnitus. However, the corresponding studies involved only small samples and analyses were restricted to the auditory cortex in most studies. Evidence is growing that also limbic, frontal, and parietal areas are involved in the pathophysiology of chronic tinnitus. These regions are considered to mediate perceptual, attentional, and emotional processes. Thus, the aim of the present study was the systematic evaluation of metabolic brain activity in a large sample of tinnitus patients. Ninety one patients with chronic tinnitus underwent FDG‐PET. The effects of tinnitus severity (assessed by a tinnitus questionnaire score), duration and laterality were evaluated with statistical parametric mapping (SPM) in whole brain analyses. In addition, region of interest analyses were performed for primary auditory areas. Tinnitus duration correlated positively with brain metabolism in right inferior frontal, right ventro‐medial prefrontal, and right posterior cingulate cortex. Tinnitus distress correlated positively with activation of left and right posterior inferior temporal gyrus as well as left and right posterior parahippocampal–hippocampal interface. Region of interest analysis demonstrated an overactivation of left in contrast to right Heschls gyrus independently from tinnitus laterality and anatomical hemispheric differences. Tinnitus duration and distress were associated with areas involved in attentional and emotional processing. This is in line with recent findings indicating the relevance of higher order areas in the pathophysiology of tinnitus. Earlier results of asymmetric activation of the auditory cortices in tinnitus were confirmed, i.e., left‐sided overactivation was found independently from tinnitus laterality. Hum Brain Mapp, 2013.

Functional neuroimaging of attention in the auditory modality.

PREVIOUS functional neuroimaging studies of attention have emphasized the visual modality. We developed an auditory version of the continuous performance test (CPT) that included simple, focused and divided attention conditions. Positron emission tomographic (PET) scans were acquired during CPT performance in normal young adults and then submitted to statistical parametric mapping. Simple attention brought about a large region of activation involving the anterior cingulate gyrus and the right anterior/mesial frontal lobe. Focused and divided attention CPT conditions were compared but there were few significant differences. The findings are consistent with activation of an anterior attention network during auditory attention, without involvement of posterior attention structures which are more likely to vary in accordance with sensory modality.

PET imaging of the normal human auditory system: responses to speech in quiet and in background noise

The neural mechanisms involved in listening to sentences, and then detecting and verbalizing a specific word are poorly understood, but most likely involve complex neural networks. We used positron emission tomography to identify the areas of the human brain that are activated when young, normal hearing males and females were asked to listen to a sentence and repeat the last word from the Speech in Noise (SPIN) test. Listening conditions were (1) Quiet, (2) Speech, (3) Noise, and (4) SPIN with stimuli presented monaurally to either the left ear or the right ear. The least difficult listening task, Speech, resulted in bilateral activation of superior and middle temporal gyrus and pre-central gyrus. The Noise and SPIN conditions activated many of the same regions as Speech alone plus additional sites within the cerebellum, thalamus and superior/middle frontal gyri. Comparison of the SPIN condition versus Speech revealed additional activation in the right anterior lobe of the cerebellum and right medial frontal gyrus, near the cingulate. None of the left ear-right ear stimulus comparison revealed any significant differences except for the SPIN condition that showed greater activation in the left superior temporal gyrus for stimuli presented to the right ear. No gender differences were observed. These results demonstrate that repeating the last word in a sentence activates mainly auditory and motor areas of the brain when Speech is presented, whereas more difficult tasks, such as SPIN or multi-talker Noise, activate linguistic, attentional, cognitive, working memory, and motor planning areas.

Exercise Treatment for Postconcussion Syndrome: A Pilot Study of Changes in Functional Magnetic Resonance Imaging Activation, Physiology, and Symptoms

Purpose:To compare functional magnetic resonance imaging (fMRI) activation patterns during a cognitive task, exercise capacity, and symptoms in postconcussion syndrome (PCS) patients who received exercise treatment (n = 4) with a PCS placebo stretching group (n = 4) and a healthy control group (n = 4). Methods:Subjects completed a math processing task during fMRI and an exercise treadmill test before (time 1) and after approximately 12 weeks (time 2). Exercise subjects performed aerobic exercise at 80% of the heart rate (HR) attained on the treadmill test, 20 minutes per day with an HR monitor at home, 6 days per week. The program was modified as the HR for symptom exacerbation increased. Results:At time 1, there was no difference in fMRI activation between the 2 PCS groups but healthy controls had significantly greater activation in the posterior cingulate gyrus, lingual gyrus, and cerebellum versus all PCS subjects (P < .05, corrected for multiple comparisons). At time 2, exercise PCS did not differ from healthy controls whereas placebo stretching PCS had significantly less activity in the cerebellum (P < .05 corrected) and in the anterior cingulate gyrus and thalamus (P < .001, uncorrected) versus healthy controls. At time 2, exercise PCS achieved a significantly greater exercise HR (P < .001) and had fewer symptoms (P < .0004) than placebo stretching PCS. Cognitive performance did not differ by group or time. Conclusions:Controlled aerobic exercise rehabilitation may help restore normal cerebral blood flow regulation, as indicated by fMRI activation, in PCS patients. The PCS symptoms may be related to abnormal cerebral blood flow regulation.

Metabolic imaging of rat brain during pharmacologically-induced tinnitus

Although much is known about the perceptual characteristics of tinnitus, its neural origins remain poorly understood. We investigated the pattern of neural activation in central auditory structures using positron emission tomography (PET) imaging in a rat model of salicylate-induced tinnitus. Awake rats were injected with the metabolic tracer, fluorine-18 fluorodeoxyglucose (FDG), once in a quiet state (baseline) and once during salicylate-induced tinnitus. Tinnitus was verified using a behavioral technique. Brain imaging was performed using a high-resolution microPET scanner. Rats underwent magnetic resonance imaging (MRI) and reconstructed MRI and microPET images were fused to identify brain structures. FDG activity in brain regions of interest were quantified and compared. MicroPET imaging showed that FDG activity in the frontal pole was stable between baseline and tinnitus conditions, suggesting it was metabolically inert during tinnitus. Inferior colliculi (p=0.03) and temporal cortices (p=0.003) showed significantly increased FDG activity during tinnitus relative to baseline; activity in the colliculi and temporal cortices increased by 17%+/-21% and 29%+/-20%, respectively. FDG activity in the thalami also increased during tinnitus, but the increase did not reach statistical significance (p=0.07). Our results show increased metabolic activity consistent with neuronal activation in inferior colliculi and auditory cortices of rats during salicylate-induced tinnitus. These results are the first to show that microPET imaging can be used to identify central auditory structures involved in tinnitus and suggest that microPET imaging might be used to evaluate the therapeutic potential of drugs to treat tinnitus.

Mapping the neural systems that mediate the Paced Auditory Serial Addition Task (PASAT).

The paced auditory serial addition task (PASAT), in which subjects hear a number-string and add the two most-recently heard numbers, is a neuropsychological test sensitive to cerebral dysfunction. We mapped the brain regions activated by the PASAT using positron emission tomography (PET) and 15O-water to measure cerebral blood flow. We parsed the PASAT by mapping sites activated by immediate repetition of numbers and by repetition of the prior number after the presentation of the next number in the series. The PASAT activated dispersed non-contiguous foci in the superior temporal gyri, bifrontal and biparietal sites, the anterior cingulate and bilateral cerebellar sites. These sites are consistent with the elements of the task that include auditory perception and processing, speech production, working memory, and attention. Sites mediating addition were not identified. The extent of the sites activated during the performance of the PASAT accounts for the sensitivity of this test and justifies its use in a variety of seemingly disparate conditions.