Timm B. Poeppl

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.

Can Temporal Repetitive Transcranial Magnetic Stimulation be Enhanced by Targeting Affective Components of Tinnitus with Frontal rTMS? A Randomized Controlled Pilot Trial.

Objectives: Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex has been investigated as a new treatment tool for chronic tinnitus during the last years and has shown moderate efficacy. However, there is growing evidence that tinnitus is not a pathology of a specific brain region, but rather the result of network dysfunction involving both auditory and non-auditory brain regions. In functional imaging studies the right dorsolateral prefrontal cortex has been identified as an important hub in tinnitus related networks and has been shown to particularly reflect the affective components of tinnitus. Based on these findings we aimed to investigate whether the effects of left low-frequency rTMS can be enhanced by antecedent right prefrontal low-frequency rTMS. Study Design: Fifty-six patients were randomized to receive either low-frequency left temporal rTMS or a combination of low-frequency right prefrontal followed by low-frequency left temporal rTMS. The change of the tinnitus questionnaire (TQ) score was the primary outcome, secondary outcome parameters included the Tinnitus Handicap Inventory, numeric rating scales, and the Beck Depression Inventory. The study is registered in clinicaltrials.gov (NCT01261949). Results: Directly after therapy there was a significant improvement of the TQ-score in both groups. Comparison of both groups revealed a trend toward more pronounced effects for the combined group (effect size: Cohen’s d = 0.176), but this effect did not reach significance. A persistent trend toward better efficacy was also observed in all other outcome criteria. Conclusion: Additional stimulation of the right prefrontal cortex seems to be a promising strategy for enhancing TMS effects over the temporal cortex. These results further support the involvement of the right DLPFC in the pathophysiology of tinnitus. The small effect size might be due to the study design comparing the protocol to an active control condition.

Neuroimaging and neuromodulation: complementary approaches for identifying the neuronal correlates of tinnitus.

An inherent limitation of functional imaging studies is their correlational approach. More information about critical contributions of specific brain regions can be gained by focal transient perturbation of neural activity in specific regions with non-invasive focal brain stimulation methods. Functional imaging studies have revealed that tinnitus is related to alterations in neuronal activity of central auditory pathways. Modulation of neuronal activity in auditory cortical areas by repetitive transcranial magnetic stimulation (rTMS) can reduce tinnitus loudness and, if applied repeatedly, exerts therapeutic effects, confirming the relevance of auditory cortex activation for tinnitus generation and persistence. Measurements of oscillatory brain activity before and after rTMS demonstrate that the same stimulation protocol has different effects on brain activity in different patients, presumably related to interindividual differences in baseline activity in the clinically heterogeneous study cohort. In addition to alterations in auditory pathways, imaging techniques also indicate the involvement of non-auditory brain areas, such as the fronto-parietal “awareness” network and the non-tinnitus-specific distress network consisting of the anterior cingulate cortex, anterior insula, and amygdale. Involvement of the hippocampus and the parahippocampal region putatively reflects the relevance of memory mechanisms in the persistence of the phantom percept and the associated distress. Preliminary studies targeting the dorsolateral prefrontal cortex, the dorsal anterior cingulate cortex, and the parietal cortex with rTMS and with transcranial direct current stimulation confirm the relevance of the mentioned non-auditory networks. Available data indicate the important value added by brain stimulation as a complementary approach to neuroimaging for identifying the neuronal correlates of the various clinical aspects of tinnitus.

Transcutaneous vagus nerve stimulation: retrospective assessment of cardiac safety in a pilot study.

Background: Vagus nerve stimulation has been successfully used as a treatment strategy for epilepsy and affective disorders for years. Transcutaneous vagus nerve stimulation (tVNS) is a new non-invasive method to stimulate the vagus nerve, which has been shown to modulate neuronal activity in distinct brain areas. Objectives: Here we report effects of tVNS on cardiac function from a pilot study, which was conducted to evaluate the feasibility and safety of tVNS for the treatment of chronic tinnitus. Methods: Twenty-four patients with chronic tinnitus underwent treatment with tVNS over 3–10 weeks in an open single-armed pilot study. Safety criteria and practical usability of the neurostimulating device were to investigate by clinical examination and electrocardiography at baseline and at several visits during and after tVNS treatment (week 2, 4, 8, 16, and 24). Results: Two adverse cardiac events (one classified as a severe adverse event) were registered but considered very unlikely to have been caused by the tVNS device. Retrospective analyses of electrocardiographic parameters revealed a trend toward shortening of the QRS complex after tVNS. Conclusion: To our knowledge this is one of the first studies investigating feasibility and safety of tVNS in a clinical sample. In those subjects with no known pre-existing cardiac pathology, preliminary data do not indicate arrhythmic effects of tVNS.

The functional neuroanatomy of male psychosexual and physiosexual arousal: A quantitative meta-analysis

Reproductive behavior is mandatory for conservation of species and mediated by a state of sexual arousal (SA), involving both complex mental processes and bodily reactions. An early neurobehavioral model of SA proposes cognitive, emotional, motivational, and autonomic components. In a comprehensive quantitative meta‐analysis on previous neuroimaging findings, we provide here evidence for distinct brain networks underlying psychosexual and physiosexual arousal. Psychosexual (i.e., mental sexual) arousal recruits brain areas crucial for cognitive evaluation, top‐down modulation of attention and exteroceptive sensory processing, relevance detection and affective evaluation, as well as regions implicated in the representation of urges and in triggering autonomic processes. In contrast, physiosexual (i.e., physiological sexual) arousal is mediated by regions responsible for regulation and monitoring of initiated autonomic processes and emotions and for somatosensory processing. These circuits are interconnected by subcortical structures (putamen and claustrum) that provide exchange of sensorimotor information and crossmodal processing between and within the networks. Brain deactivations may imply attenuation of introspective processes and social cognition, but be necessary to release intrinsic inhibition of SA. Hum Brain Mapp 35:1404–1421, 2014.

Functional Cortical and Subcortical Abnormalities in Pedophilia: A Combined Study Using a Choice Reaction Time Task and fMRI

INTRODUCTION Pedophiles show sexual interest in prepubescent children but not in adults. Research into the neurofunctional mechanisms of paraphilias has gathered momentum over the last years. AIM To elucidate the underlying neural processing of sexual interest among pedophiles and to highlight the differences in comparison with nonparaphilic sexual interest in adults. METHODS Nine pedophilic patients and 11 nonpedophilic control subjects underwent functional magnetic resonance imaging (fMRI) while viewing pictures of nude (prepubescents, pubescents, and adults) and neutral content, as well as performing a concomitant choice reaction time task (CRTT). MAIN OUTCOME MEASURES Brain blood oxygen level-dependent (BOLD) signals and response latencies in the CRTT during exposure to each picture category. RESULTS Analysis of behavioral data showed group differences in reaction times regarding prepubescent and adult but not pubescent stimuli. During stimulation with pictures displaying nude prepubescents, pedophiles showed increased BOLD response in brain areas known to be involved in processing of visual sexual stimuli. Comparison of pedophilic patients with the control group discovered differences in BOLD responses with respect to prepubescent and adult but not to pubescent stimuli. Differential effects in particular occurred in the cingulate gyrus and insular region. CONCLUSIONS The brain response of pedophiles to visual sexual stimulation by images of nude prepubescents is comparable with previously described neural patterns of sexual processing in nonpedophilic human males evoked by visual stimuli depicting nude adults. Nevertheless, group differences found in the cingulate gyrus and the insular region suggest an important role of these brain areas in pedophilic sexual interest. Furthermore, combining attention-based methods like CRTT with fMRI may be a viable option for future diagnostic procedures regarding pedophilia.

Hypothermia Associated With Antipsychotic Drug Use: A Clinical Case Series and Review of Current Literature

Hypothermia as an adverse reaction of antipsychotic drug use represents a potentially life‐threatening complication. However, the mechanisms by which antipsychotic drugs alter thermoregulatory processes in the human body are far from being fully understood. Here we present a case series of 5 patients developing severe hypothermia after administration of olanzapine and benperidol. Controlled by a network of neural structures, body temperature is physiologically regulated in far more narrow boundaries than are other vital functions, and its homeostasis is critical for survival. The preoptic region in the ventral hypothalamus is assumed to act as a coordinating center that is endowed with thermosensory units that constantly compare actual body temperature with target values and initiate regulatory and compensatory mechanisms in case of mismatch. Hypothermia risk seems to increase in the first days after initiation of antipsychotic drug therapy or increases in the daily dose. Schizophrenic patients bear a higher risk than nonschizophrenic patients treated with antipsychotic drugs (such as patients with dementia or depression). Antipsychotic drugs with strong 5‐HT2 antagonism seem to be more frequently associated with hypothermia. These cases demonstrate the clinical relevance of hypothermia as an adverse reaction to antipsychotic treatment and the importance of careful monitoring of body temperature.

Association between brain structure and phenotypic characteristics in pedophilia

Studies applying structural neuroimaging to pedophiles are scarce and have shown conflicting results. Although first findings suggested reduced volume of the amygdala, pronounced gray matter decreases in frontal regions were observed in another group of pedophilic offenders. When compared to non-sexual offenders instead of community controls, pedophiles revealed deficiencies in white matter only. The present study sought to test the hypotheses of structurally compromised prefrontal and limbic networks and whether structural brain abnormalities are related to phenotypic characteristics in pedophiles. We compared gray matter volume of male pedophilic offenders and non-sexual offenders from high-security forensic hospitals using voxel-based morphometry in cross-sectional and correlational whole-brain analyses. The significance threshold was set to p < .05, corrected for multiple comparisons. Compared to controls, pedophiles exhibited a volume reduction of the right amygdala (small volume corrected). Within the pedophilic group, pedosexual interest and sexual recidivism were correlated with gray matter decrease in the left dorsolateral prefrontal cortex (r = -.64) and insular cortex (r = -.45). Lower age of victims was strongly associated with gray matter reductions in the orbitofrontal cortex (r = .98) and angular gyri bilaterally (r = .70 and r = .93). Our findings of specifically impaired neural networks being related to certain phenotypic characteristics might account for the heterogeneous results in previous neuroimaging studies of pedophilia. The neuroanatomical abnormalities in pedophilia seem to be of a dimensional rather than a categorical nature, supporting the notion of a multifaceted disorder.

Predictors for rTMS response in chronic tinnitus

Background: Repetitive transcranial magnetic stimulation (rTMS) has been studied as a treatment option for chronic tinnitus for almost 10 years now. Although most of these studies have demonstrated beneficial effects, treatment results show high interindividual variability and yet, little is known about predictors for treatment response. Methods: Data from 538 patients with chronic tinnitus were analyzed. Patients received either low-frequency rTMS over the left temporal cortex (n = 345, 1 Hz, 110% motor threshold, 2000 stimuli/day) or combined temporal and frontal stimulation (n = 193, 110% motor threshold, 2000 stimuli at 20 Hz over left dorsolateral prefrontal cortex plus 2000 stimuli at 1 Hz over temporal cortex). Numerous demographic, clinical, and audiological variables as well as different tinnitus characteristics were analyzed as potential predictors for treatment outcome, which was defined as change in the tinnitus questionnaire (TQ) score. Results: Both stimulation protocols resulted in a significant decrease of TQ scores. Effect sizes were small, however. In the group receiving combined treatment, patients with comorbid temporomandibular complaints benefited more from rTMS than patients without those complaints. In addition, patients with higher TQ scores at baseline had more pronounced TQ reductions than patients with low TQ baseline scores. Also, patients who had already improved from screening to baseline benefited less than patients without initial improvement. Conclusions: The results from this large sample demonstrate that rTMS shows only small but clinically significant effects in the treatment of chronic tinnitus. There are no good demographic or clinical predictors for treatment outcome.

Feasibility, Safety and Efficacy of Transcutaneous Vagus Nerve Stimulation in Chronic Tinnitus: An Open Pilot Study

OBJECTIVES Vagus nerve stimulation represents an established treatment strategy for epilepsy and affective disorders. Recently, positive effects were also shown in animals and humans with tinnitus. Here we report the results of an open pilot study exploring feasibility, safety and efficacy of tVNS in the treatment of chronic tinnitus. STUDY DESIGN Fifty patients with chronic tinnitus underwent tVNS in an open single-armed pilot study which was conducted in two phases applying two different stimulating devices (Cerbomed CM02 and NEMOS). Clinical assessment was based on Tinnitus Questionnaire (TQ), Tinnitus Handicap Inventory (THI), Beck Depression Inventory (BDI), WHO Quality of Life, and various numeric rating scales. Primary outcome was defined as change in TQ (baseline vs. final visit in week 24). The study has been registered with clinicaltrials.gov (NCT01176734). RESULTS Primary analysis indicated mean TQ reductions of 3.7 points (phase 1) and 2.8 points (phase 2) significant for the first study phase. Secondary analyses indicated a significant BDI reduction for phase 1 (uncorrected for multiple testing), but no further systematic or significant effects. Adverse events included twitching and pressure at electrode placement site. The occurrence of one hospitalization because of palpations and the development of a left bundle branch block were considered as unrelated to the intervention. Cognitive testing revealed no significant changes. CONCLUSION Our data demonstrate the feasibility of tVNS over a period of 6 months. There was no clinically relevant improvement of tinnitus complaints. Our data suggest tVNS to be considered safe in patients without a history of cardiac disease.