Association between fatigue, peripheral serotonin, and L-carnitine in hypothyroidism and in chronic fatigue syndrome.

Background: Fatigue of unknown origin is a hallmark symptom in chronic fatigue syndrome (CFS) and is also found in 20% of hypothyroidism patients despite appropriate levothyroxine treatment. Here, we suggest that in these disorders, peripheral serotonin levels are low, and elevating them to normal range with L-carnitine is accompanied with reduced fatigue. Methods: We conducted a retrospective analysis of follow-up clinical data (CFS N=12; hypothyroidism with fatigue N=40) where serum serotonin and fatigue levels were compared before vs. after 7 weeks of oral L-carnitine supplementation. Results: After L-carnitine, serotonin increased (8-fold in CFS, Sig. = 0.002, 6-fold in hypothyroidism, Sig. < 0.001) whereas fatigue decreased (2-fold in both CFS and hypothyroidism, Sig. = 0.002 for CFS, Sig. < 0.001 for hypothyroidism). There was a negative correlation between serotonin level and fatigue (for CFS, rho = -0.49 before and -0.67 after L-carnitine; for hypothyroidism, rho = -0.24 before and -0.83 after L-carnitine). Conclusions: These findings suggest a new link between low peripheral serotonin, L-carnitine, and fatigue.

Cortical depth profiles of auditory and visual 7 T functional MRI responses in human superior temporal areas.

Invasive neurophysiological studies in nonhuman primates have shown different laminar activation profiles to auditory vs. visual stimuli in auditory cortices and adjacent polymodal areas. Means to examine the underlying feedforward vs. feedback type influences noninvasively have been limited in humans. Here, using 1-mm isotropic resolution 3D echo-planar imaging at 7 T, we studied the intracortical depth profiles of functional magnetic resonance imaging (fMRI) blood oxygenation level dependent (BOLD) signals to brief auditory (noise bursts) and visual (checkerboard) stimuli. BOLD percent-signal-changes were estimated at 11 equally spaced intracortical depths, within regions-of-interest encompassing auditory (Heschl's gyrus, Heschl's sulcus, planum temporale, and posterior superior temporal gyrus) and polymodal (middle and posterior superior temporal sulcus) areas. Effects of differing BOLD signal strengths for auditory and visual stimuli were controlled via normalization and statistical modeling. The BOLD depth profile shapes, modeled with quadratic regression, were significantly different for auditory vs. visual stimuli in auditory cortices, but not in polymodal areas. The different depth profiles could reflect sensory-specific feedforward versus cross-sensory feedback influences, previously shown in laminar recordings in nonhuman primates. The results suggest that intracortical BOLD profiles can help distinguish between feedforward and feedback type influences in the human brain. Further experimental studies are still needed to clarify how underlying signal strength influences BOLD depth profiles under different stimulus conditions.

A Quasi-Static Boundary Element Approach With Fast Multipole Acceleration for High-Resolution Bioelectromagnetic Models.

OBJECTIVE: We develop a new accurate version of the boundary element fast multipole method for transcranial magnetic stimulation (TMS) related problems. This method is based on the surface-charge formulation and is using the highly efficient fast multipole accelerator along with analytical computations of neighbor surface integrals. RESULTS: The method accuracy is demonstrated by comparison with the proven commercial finite-element method (FEM) software ANSYS Maxwell 18.2 2017 operating on unstructured grids and with adaptive mesh refinement. Five realistic high-definition head models from the Population Head Repository (IT'IS Foundation, Switzerland) have been acquired and augmented with a commercial TMS coil model (MRi-B91, MagVenture, Denmark). For each head model, simulations with our method and simulations with the FEM software ANSYS Maxwell 18.2 2017 have been performed. These simulations have been compared with each other and an excellent agreement was established in every case. SIGNIFICANCE: At the same time, our new method runs approximately 500 times faster than the ANSYS FEM, finishes in about 200 s on a standard server, and naturally provides a submillimeter field resolution, which is justified using mesh refinement. CONCLUSIONS: Our method can be applied to modeling of brain stimulation and recording technologies such as TMS and magnetoencephalography, and has the potential to become a real-time high-resolution simulation tool.

Evidence for distinct human auditory cortex regions for sound location versus identity processing.

Neurophysiological animal models suggest that anterior auditory cortex (AC) areas process sound identity information, whereas posterior ACs specialize in sound location processing. In humans, inconsistent neuroimaging results and insufficient causal evidence have challenged the existence of such parallel AC organization. Here we transiently inhibit bilateral anterior or posterior AC areas using MRI-guided paired-pulse transcranial magnetic stimulation (TMS) while subjects listen to Reference/Probe sound pairs and perform either sound location or identity discrimination tasks. The targeting of TMS pulses, delivered 55-145 ms after Probes, is confirmed with individual-level cortical electric-field estimates. Our data show that TMS to posterior AC regions delays reaction times (RT) significantly more during sound location than identity discrimination, whereas TMS to anterior AC regions delays RTs significantly more during sound identity than location discrimination. This double dissociation provides direct causal support for parallel processing of sound identity features in anterior AC and sound location in posterior AC.

Neuronal representations of distance in human auditory cortex.

Neuronal mechanisms of auditory distance perception are poorly understood, largely because contributions of intensity and distance processing are difficult to differentiate. Typically, the received intensity increases when sound sources approach us. However, we can also distinguish between soft-but-nearby and loud-but-distant sounds, indicating that distance processing can also be based on intensity-independent cues. Here, we combined behavioral experiments, fMRI measurements, and computational analyses to identify the neural representation of distance independent of intensity. In a virtual reverberant environment, we simulated sound sources at varying distances (15-100 cm) along the right-side interaural axis. Our acoustic analysis suggested that, of the individual intensity-independent depth cues available for these stimuli, direct-to-reverberant ratio (D/R) is more reliable and robust than interaural level difference (ILD). However, on the basis of our behavioral results, subjects' discrimination performance was more consistent with complex intensity-independent distance representations, combining both available cues, than with representations on the basis of either D/R or ILD individually. fMRI activations to sounds varying in distance (containing all cues, including intensity), compared with activations to sounds varying in intensity only, were significantly increased in the planum temporale and posterior superior temporal gyrus contralateral to the direction of stimulation. This fMRI result suggests that neurons in posterior nonprimary auditory cortices, in or near the areas processing other auditory spatial features, are sensitive to intensity-independent sound properties relevant for auditory distance perception.

Dissociable influences of auditory object vs. spatial attention on visual system oscillatory activity.

Given that both auditory and visual systems have anatomically separate object identification ("what") and spatial ("where") pathways, it is of interest whether attention-driven cross-sensory modulations occur separately within these feature domains. Here, we investigated how auditory "what" vs. "where" attention tasks modulate activity in visual pathways using cortically constrained source estimates of magnetoencephalograpic (MEG) oscillatory activity. In the absence of visual stimuli or tasks, subjects were presented with a sequence of auditory-stimulus pairs and instructed to selectively attend to phonetic ("what") vs. spatial ("where") aspects of these sounds, or to listen passively. To investigate sustained modulatory effects, oscillatory power was estimated from time periods between sound-pair presentations. In comparison to attention to sound locations, phonetic auditory attention was associated with stronger alpha (7-13 Hz) power in several visual areas (primary visual cortex; lingual, fusiform, and inferior temporal gyri, lateral occipital cortex), as well as in higher-order visual/multisensory areas including lateral/medial parietal and retrosplenial cortices. Region-of-interest (ROI) analyses of dynamic changes, from which the sustained effects had been removed, suggested further power increases during Attend Phoneme vs. Location centered at the alpha range 400-600 ms after the onset of second sound of each stimulus pair. These results suggest distinct modulations of visual system oscillatory activity during auditory attention to sound object identity ("what") vs. sound location ("where"). The alpha modulations could be interpreted to reflect enhanced crossmodal inhibition of feature-specific visual pathways and adjacent audiovisual association areas during "what" vs. "where" auditory attention.

Onset timing of cross-sensory activations and multisensory interactions in auditory and visual sensory cortices.

Here we report early cross-sensory activations and audiovisual interactions at the visual and auditory cortices using magnetoencephalography (MEG) to obtain accurate timing information. Data from an identical fMRI experiment were employed to support MEG source localization results. Simple auditory and visual stimuli (300-ms noise bursts and checkerboards) were presented to seven healthy humans. MEG source analysis suggested generators in the auditory and visual sensory cortices for both within-modality and cross-sensory activations. fMRI cross-sensory activations were strong in the visual but almost absent in the auditory cortex; this discrepancy with MEG possibly reflects the influence of acoustical scanner noise in fMRI. In the primary auditory cortices (Heschl's gyrus) the onset of activity to auditory stimuli was observed at 23 ms in both hemispheres, and to visual stimuli at 82 ms in the left and at 75 ms in the right hemisphere. In the primary visual cortex (Calcarine fissure) the activations to visual stimuli started at 43 ms and to auditory stimuli at 53 ms. Cross-sensory activations thus started later than sensory-specific activations, by 55 ms in the auditory cortex and by 10 ms in the visual cortex, suggesting that the origins of the cross-sensory activations may be in the primary sensory cortices of the opposite modality, with conduction delays (from one sensory cortex to another) of 30-35 ms. Audiovisual interactions started at 85 ms in the left auditory, 80 ms in the right auditory and 74 ms in the visual cortex, i.e., 3-21 ms after inputs from the two modalities converged.

Primary and multisensory cortical activity is correlated with audiovisual percepts.

Incongruent auditory and visual stimuli can elicit audiovisual illusions such as the McGurk effect where visual /ka/ and auditory /pa/ fuse into another percept such as/ta/. In the present study, human brain activity was measured with adaptation functional magnetic resonance imaging to investigate which brain areas support such audiovisual illusions. Subjects viewed trains of four movies beginning with three congruent /pa/ stimuli to induce adaptation. The fourth stimulus could be (i) another congruent /pa/, (ii) a congruent /ka/, (iii) an incongruent stimulus that evokes the McGurk effect in susceptible individuals (lips /ka/ voice /pa/), or (iv) the converse combination that does not cause the McGurk effect (lips /pa/ voice/ ka/). This paradigm was predicted to show increased release from adaptation (i.e. stronger brain activation) when the fourth movie and the related percept was increasingly different from the three previous movies. A stimulus change in either the auditory or the visual stimulus from /pa/ to /ka/ (iii, iv) produced within-modality and cross-modal responses in primary auditory and visual areas. A greater release from adaptation was observed for incongruent non-McGurk (iv) compared to incongruent McGurk (iii) trials. A network including the primary auditory and visual cortices, nonprimary auditory cortex, and several multisensory areas (superior temporal sulcus, intraparietal sulcus, insula, and pre-central cortex) showed a correlation between perceiving the McGurk effect and the fMRI signal, suggesting that these areas support the audiovisual illusion.

Mind's ear in a musician: where and when in the brain.

The temporospatial pattern of brain activity during auditory imagery was studied using magnetoencephalography. Trained musicians were presented with visual notes and instructed to imagine the corresponding sounds. Brain activity specific to the auditory imagery task was observed, first as enhanced activity of left and right occipital areas (average onset 120-150 ms after the onset of the visual stimulus) and then spreading to the midline parietal cortex (precuneus) and to such extraoccipital areas that were not activated during the visual control condition (e.g., the left temporal auditory association cortex and the left and right premotor cortices). The latest activations, with average onset latencies of 270-400 ms clearly separate from the earliest ones, occurred in the left sensorimotor cortex and the right inferotemporal visual association cortex. These data imply a complex temporospatial activation sequence of multiple cortical areas when musicians recall firmly established audiovisual associations.