Limbic self-neuromodulation as a novel treatment option for emotional dysregulation in premenstrual dysphoric disorder (PMDD); a proof-of-concept study.

AIM: To assess the efficacy of a novel neurofeedback (NF) method, targeting limbic activity, to treat emotional dysregulation related to premenstrual dysphoric disorder (PMDD). METHODS: We applied a NF probe targeting limbic activity using a functional magnetic resonance imaging-inspired electroencephalogram model (termed Amyg-EFP-NF) in a double-blind randomized controlled trial. A frontal alpha asymmetry probe (AAS-NF), served as active control. Twenty-seven participants diagnosed with PMDD (mean age = 33.57 years, SD = 5.67) were randomly assigned to Amyg-EFP-NF or AAS-NF interventions with a 2:1 ratio, respectively. The treatment protocol consisted of 11 NF sessions through three menstrual cycles, and a follow-up assessment 3 months thereafter. The primary outcome measure was improvement in the Revised Observer Version of the Premenstrual Tension Syndrome Rating Scale (PMTS-OR). RESULTS: A significant group by time effect was observed for the core symptom subscale of the PMTS-OR, with significant improvement observed at follow-up for the Amyg-EFP group compared with the AAS group [F(1, 15)=4.968, P = 0.042]. This finding was specifically robust for reduction in anger [F(1, 15) = 22.254, P < 0.001]. A significant correlation was found between learning scores and overall improvement in core symptoms (r = 0.514, P = 0.042) suggesting an association between mechanism of change and clinical improvement. CONCLUSION: Our preliminary findings suggest that Amyg-EFP-NF may serve as an affordable and accessible non-invasive treatment option for emotional dysregulation in women suffering from PMDD. Our main limitations were the relatively small number of participants and the lack of a sham-NF placebo arm.

Somatic engagement alters subsequent neurobehavioral correlates of affective mentalizing.

Socio-emotional encounters involve a resonance of others' affective states, known as affect sharing (AS); and attribution of mental states to others, known as theory-of-mind (ToM). Empathy necessitates the integration of both processes, yet their interaction during emotional episodes and subsequent generation of inferences on others' affective states has rarely been tested. To address this, we developed a novel experimental design, wherein we manipulated AS by presenting nonverbal emotionally negative movies twice-each time accompanied by one of two soundtracks that accentuated either somatic cues or externally generated sounds. Movies were followed by questions addressing affective-ToM (emotional inferences), cognitive-ToM (inferences on beliefs and knowledge), and non-ToM aspects. Results revealed a neural differentiation between AS, affective-ToM, and cognitive-ToM. AS movies activated regions that have been implicated in emotional (e.g., amygdala) and somatosensory processing, and synchronized brain activity between participants in the latter. Affective-ToM activated the middle insula, limbic regions, and both ventral and dorsal portions of the medial prefrontal cortex (ventral medial prefrontal cortex [VMPFC] and dorsal medial prefrontal cortex [DMPFC], respectively), whereas cognitive-ToM activated posteromedial and lateral-prefrontal and temporal cortices. Critically, AS movies specifically altered neural activation in AS and ToM-related regions during subsequent affective-ToM inferences, most notably in the DMPFC. Moreover, DMPFC-VMPFC connectivity correlated with affective-ToM accuracy, when such questions followed AS movies. Our results associate empathic processes with designated neural activations and shed light on how neuro-behavioral indices of affective ToM are shaped by preceding somatic engagement.

Vocal Biomarker Is Associated With Hospitalization and Mortality Among Heart Failure Patients.

Background The purpose of this article is to evaluate the association of voice signal analysis with adverse outcome among patients with congestive heart failure (CHF). Methods and Results The study cohort included 10 583 patients who were registered to a call center of patients who had chronic conditions including CHF in Israel between 2013 and 2018. A total of 223 acoustic features were extracted from 20 s of speech for each patient. A biomarker was developed based on a training cohort of non-CHF patients (N=8316). The biomarker was tested on a mutually exclusive CHF study cohort (N=2267) and was evaluated as a continuous and ordinal (4 quartiles) variable. Median age of the CHF study population was 77 (interquartile range 68-83) and 63% were men. During a median follow-up of 20 months (interquartile range 9-34), 824 (36%) patients died. Kaplan-Meier survival analysis showed higher cumulative probability of death with increasing quartiles (23%, 29%, 38%, and 54%; P<0.001). Survival analysis with adjustment to known predictors of poor survival demonstrated that each SD increase in the biomarker was associated with a significant 32% increased risk of death during follow-up (95% CI, 1.24-1.41, P<0.001) and that compared with the lowest quartile, patients in the highest quartile were 96% more likely to die (95% CI, 1.59-2.42, P<0.001). The model consistently demonstrated an independent association of the biomarker with hospitalizations during follow-up (P<0.001). Conclusions Noninvasive vocal biomarker is associated with adverse outcome among CHF patients, suggesting a possible role for voice analysis in telemedicine and CHF patient care.

Intra-operative multi-site stimulation: Expanding methodology for cortical brain mapping of language functions.

Direct cortical stimulation (DCS) is considered the gold-standard for functional cortical mapping during awake surgery for brain tumor resection. DCS is performed by stimulating one local cortical area at a time. We present a feasibility study using an intra-operative technique aimed at improving our ability to map brain functions which rely on activity in distributed cortical regions. Following standard DCS, Multi-Site Stimulation (MSS) was performed in 15 patients by applying simultaneous cortical stimulations at multiple locations. Language functioning was chosen as a case-cognitive domain due to its relatively well-known cortical organization. MSS, performed at sites that did not produce disruption when applied in a single stimulation point, revealed additional language dysfunction in 73% of the patients. Functional regions identified by this technique were presumed to be significant to language circuitry and were spared during surgery. No new neurological deficits were observed in any of the patients following surgery. Though the neuro-electrical effects of MSS need further investigation, this feasibility study may provide a first step towards sophistication of intra-operative cortical mapping.

Probabilistic machine learning for the evaluation of presurgical language dominance.

OBJECTIVE Providing a reliable assessment of language lateralization is an important task to be performed prior to neurosurgery in patients with epilepsy. Over the last decade, functional MRI (fMRI) has emerged as a useful noninvasive tool for language lateralization, supplementing or replacing traditional invasive methods. In standard practice, fMRI-based language lateralization is assessed qualitatively by visual inspection of fMRI maps at a specific chosen activation threshold. The purpose of this study was to develop and evaluate a new computational technique for providing the probability of each patient to be left, right, or bilateral dominant in language processing. METHODS In 76 patients with epilepsy, a language lateralization index was calculated using the verb-generation fMRI task over a wide range of activation thresholds (from a permissive threshold, analyzing all brain regions, to a harsh threshold, analyzing only the strongest activations). The data were classified using a probabilistic logistic regression method. RESULTS Concordant results between fMRI and Wada lateralization were observed in 89% of patients. Bilateral and right-dominant groups showed similar fMRI lateralization patterns differentiating them from the left-dominant group but still allowing classification in 82% of patients. CONCLUSIONS These findings present the utility of a semi-supervised probabilistic learning approach for presurgical language-dominance mapping, which may be extended to other cognitive domains such as memory and attention.

Can we share the joy of others? Empathic neural responses to distress vs joy.

The neural bases of empathy have been examined mainly in the context of reacting to others' distress, while almost no attention has been paid to the mechanisms by which we share others' joy. Using functional magnetic resonance imaging, we demonstrated that the same neural network mediates judgment of the emotional state of the other in response to both negative and positive events through empathy-related structures, such as the medial prefrontal cortex (MPFC), the insula, the superior temporal sulcus (STS) and the inferior frontal gyrus (IFG). However, the responses of the MPFC, bilateral insula and the right IFG to negative experiences occurring to the other (but not to the self) were found to be much more intense than the responses to positive experiences, indicating that humans have a remarkable ability to share the distress of others, but may react less to the joy of others.

Two systems for empathy: a double dissociation between emotional and cognitive empathy in inferior frontal gyrus versus ventromedial prefrontal lesions.

Recent evidence suggests that there are two possible systems for empathy: a basic emotional contagion system and a more advanced cognitive perspective-taking system. However, it is not clear whether these two systems are part of a single interacting empathy system or whether they are independent. Additionally, the neuroanatomical bases of these systems are largely unknown. In this study, we tested the hypothesis that emotional empathic abilities (involving the mirror neuron system) are distinct from those related to cognitive empathy and that the two depend on separate anatomical substrates. Subjects with lesions in the ventromedial prefrontal (VM) or inferior frontal gyrus (IFG) cortices and two control groups were assessed with measures of empathy that incorporate both cognitive and affective dimensions. The findings reveal a remarkable behavioural and anatomic double dissociation between deficits in cognitive empathy (VM) and emotional empathy (IFG). Furthermore, precise anatomical mapping of lesions revealed Brodmann area 44 to be critical for emotional empathy while areas 11 and 10 were found necessary for cognitive empathy. These findings are consistent with these cortices being different in terms of synaptic hierarchy and phylogenetic age. The pattern of empathy deficits among patients with VM and IFG lesions represents a first direct evidence of a double dissociation between emotional and cognitive empathy using the lesion method.

Mind your left: spatial bias in subcortical fear processing.

Hemispheric lateralization of emotional processing has long been suggested, but its underlying neural mechanisms have not yet been defined. In this functional magnetic resonance imaging study, facial expressions were presented to 10 right-handed healthy adult females in an event-related visual half-field presentation paradigm. Differential activations to fearful versus neutral faces were observed in the amygdala, pulvinar, and superior colliculus only for faces presented in the left hemifield. Interestingly, the left hemifield advantage for fear processing was observed in both hemispheres. These results suggest a leftward bias in subcortical fear processing, consistent with the well-documented leftward bias of danger-associated behaviors in animals. The current finding highlights the importance of hemifield advantage in emotional lateralization, which might reflect the combination of hemispheric dominance and asymmetric interhemispheric information transfer.

Language related reorganization in adult brain with slow growing glioma: fMRI prospective case-study.

One possible mechanism for language plasticity in cases of lesions in left dominant hemisphere is the recruitment of homologous region in the unaffected non-dominant hemisphere. The potential of the right hemisphere to carry out such plasticity is expressed by the functional outcome of patients with lesions in the left hemisphere acquired at childhood prior to language acquisition. Whether lesions in the dominant hemisphere acquired in adulthood can result in functional recovery of language by means of recruitment of the non-dominant hemisphere is undetermined. We describe a 28-year-old, right-handed male diagnosed with a left temporo-frontal glioma. It was decided to manage him expectantly due to the low level of suspicion of malignancy and the close proximity of the lesion to critical language function centers. Language functional MRI (fMRI) tests were performed twice within the ensuing 2 years before surgical intervention. Regional brain activation was measured within the temporal and frontal lobes. Laterality index (LI) was calculated based on the corresponding number of activated voxels. The main finding is that over time, prior to resection of the enlarged tumor, the inferior frontal gyrus (IFG) changed from being strongly left lateralized in the first fMRI exam to being bilateral in the second fMRI exam, mainly due to larger activation in the right hemisphere. By that time, although the patient was not aphasic, his language performance was significantly below average. These findings suggest that a slow growing tumor in an adult language-related area might result in a functional reorganization by recruiting the right hemisphere. However, the contribution of such reorganization to the preservation of language performance remains equivocal.