iPSC-derived neuronal models of PANK2-associated neurodegeneration reveal mitochondrial dysfunction contributing to early disease.

Mutations in PANK2 lead to neurodegeneration with brain iron accumulation. PANK2 has a role in the biosynthesis of coenzyme A (CoA) from dietary vitamin B5, but the neuropathological mechanism and reasons for iron accumulation remain unknown. In this study, atypical patient-derived fibroblasts were reprogrammed into induced pluripotent stem cells (iPSCs) and subsequently differentiated into cortical neuronal cells for studying disease mechanisms in human neurons. We observed no changes in PANK2 expression between control and patient cells, but a reduction in protein levels was apparent in patient cells. CoA homeostasis and cellular iron handling were normal, mitochondrial function was affected; displaying activated NADH-related and inhibited FADH-related respiration, resulting in increased mitochondrial membrane potential. This led to increased reactive oxygen species generation and lipid peroxidation in patient-derived neurons. These data suggest that mitochondrial deficiency is an early feature of the disease process and can be explained by altered NADH/FADH substrate supply to oxidative phosphorylation. Intriguingly, iron chelation appeared to exacerbate the mitochondrial phenotype in both control and patient neuronal cells. This raises caution for the use iron chelation therapy in general when iron accumulation is absent.

Response and habituation of the amygdala during processing of emotional prosody.

The role of the amygdala in processing acoustic information of affective value is still under debate. Using event-related functional MRI (fMRI), we showed increased amygdalar responses to various emotions (anger, fear, happiness, eroticism) expressed by prosody, a means of communication bound to language and consequently unique to humans. The smallest signal increases were found for fearful prosody, a finding that could not be explained by rapid response habituation to stimuli of this emotional category, challenging classical theories about fear specificity of the human amygdala. Our results converge with earlier neuroimaging evidence investigating emotional vocalizations, and these neurobiological similarities suggest that the two forms of communication might have common evolutionary roots.

Differential influences of emotion, task, and novelty on brain regions underlying the processing of speech melody.

We investigated the functional characteristics of brain regions implicated in processing of speech melody by presenting words spoken in either neutral or angry prosody during a functional magnetic resonance imaging experiment using a factorial habituation design. Subjects judged either affective prosody or word class for these vocal stimuli, which could be heard for either the first, second, or third time. Voice-sensitive temporal cortices, as well as the amygdala, insula, and mediodorsal thalami, reacted stronger to angry than to neutral prosody. These stimulus-driven effects were not influenced by the task, suggesting that these brain structures are automatically engaged during processing of emotional information in the voice and operate relatively independent of cognitive demands. By contrast, the right middle temporal gyrus and the bilateral orbito-frontal cortices (OFC) responded stronger during emotion than word classification, but were also sensitive to anger expressed by the voices, suggesting that some perceptual aspects of prosody are also encoded within these regions subserving explicit processing of vocal emotion. The bilateral OFC showed a selective modulation by emotion and repetition, with particularly pronounced responses to angry prosody during the first presentation only, indicating a critical role of the OFC in detection of vocal information that is both novel and behaviorally relevant. These results converge with previous findings obtained for angry faces and suggest a general involvement of the OFC for recognition of anger irrespective of the sensory modality. Taken together, our study reveals that different aspects of voice stimuli and perceptual demands modulate distinct areas involved in the processing of emotional prosody.

Cerebral processing of emotional prosody--influence of acoustic parameters and arousal.

The human brain has a preference for processing of emotionally salient stimuli. In the auditory modality, emotional prosody can induce such involuntary biasing of processing resources. To investigate the neural correlates underlying automatic processing of emotional information in the voice, words spoken in neutral, happy, erotic, angry, and fearful prosody were presented in a passive-listening functional magnetic resonance imaging (fMRI) experiment. Hemodynamic responses in right mid superior temporal gyrus (STG) were significantly stronger for all emotional than for neutral intonations. To disentangle the contribution of basic acoustic features and emotional arousal to this activation, the relation between event-related responses and these parameters was evaluated by means of regression analyses. A significant linear dependency between hemodynamic responses of right mid STG and mean intensity, mean fundamental frequency, variability of fundamental frequency, duration, and arousal of the stimuli was observed. While none of the acoustic parameters alone explained the stronger responses of right mid STG to emotional relative to neutral prosody, this stronger responsiveness was abolished both by correcting for arousal or the conjoint effect of the acoustic parameters. In conclusion, our results demonstrate that right mid STG is sensitive to various emotions conveyed by prosody, an effect which is driven by a combination of acoustic features that express the emotional arousal in the speaker's voice.

Effects of prosodic emotional intensity on activation of associative auditory cortex.

Functional magnetic resonance imaging was used to investigate hemodynamic responses to adjectives pronounced in happy and angry intonations of varying emotional intensity. In separate sessions, participants judged the emotional valence of either intonation or semantics. To disentangle effects of emotional prosodic intensity from confounding acoustic parameters, mean and variability of volume and fundamental frequency of each stimulus were included as nuisance variables in the statistical models. A linear dependency between hemodynamic responses and emotional intensity of happy and angry intonations was found in the bilateral superior temporal sulcus during both tasks, indicating that increases of hemodynamic responses in this region are elicited by both positive and negative prosody independent of low-level acoustic properties and task instructions.