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Working memory is essential to a wide range of cognitive functions and activities. Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising method to improve working memory performance. However, the feasibility and scalability of electrical stimulation are constrained by several limitations, such as auricular discomfort and inconsistent electrical contact. We aimed to develop a novel and practical method, vibrotactile taVNS, to improve working memory. Further, we investigated its effects on arousal, measured by skin conductance and pupil diameter. This study included 20 healthy participants. Behavioral response, skin conductance, and eye tracking data were concurrently recorded while the participants performed N-back tasks under three conditions: vibrotactile taVNS delivered to the cymba concha, earlobe (sham control), and no stimulation (baseline control). In 4-back tasks, which demand maximal working memory capacity, active vibrotactile taVNS significantly improved the performance metric d ′ compared to the baseline but not to the sham. Moreover, we found that the reduction rate of d ′ with increasing task difficulty was significantly smaller during vibrotactile taVNS sessions than in both baseline and sham conditions. Arousal, measured as skin conductance and pupil diameter, declined over the course of the tasks. Vibrotactile taVNS rescued this arousal decline, leading to arousal levels corresponding to optimal working memory levels. Moreover, pupil diameter and skin conductance level were higher during high-cognitive-load tasks when vibrotactile taVNS was delivered to the concha compared to baseline and sham. Our findings suggest that vibrotactile taVNS modulates the arousal pathway and could be a potential intervention for enhancing working memory. • 6 Hz vibrotactile transcutaneous auricular vagus nerve stimulation (taVNS) increases general arousal. • 6 Hz vibrotactile taVNS mitigates arousal decreases as subjects continuously perform working memory tasks. • 6 Hz vibrotactile taVNS is a potential intervention for enhancing working memory performance. [ABSTRACT FROM AUTHOR]

• ASMs reduction was attempted in 17/27 (63%) of patients with ETLE treated with MRg-LITT. • It was successful in 12/17 (∼71%) of them. • Those who relapsed experienced significant improvement after reinstitution of ASMs. • Relapse was predicted by pre-operative seizure frequency and acute post-operative seizures. • 11% of all patients were seizure free without ASMs and 52% remained seizure free on ASMs. This study investigated the success rate of antiseizure medications (ASMs) withdrawal following MRI Guided Laser Interstitial Thermal Therapy (MRg-LITT) for extra-temporal lobe epilepsy (ETLE), and identified predictors of seizure recurrence. We retrospectively assessed 27 patients who underwent MRg-LITT for ETLE. Patients' demographics, disease characteristics, and post-surgical outcomes were evaluated for their potential to predict seizure recurrence associated with ASMs withdrawal. The median period of observation post MRg-LITT was 3 years (range 18 - 96 months) and the median period to initial ASMs reduction was 0.5 years (range 1–36 months). ASMs reduction was attempted in 17 patients (63%), 5 (29%) of whom had seizure recurrence after initial reduction. Nearly all patient who relapsed regained seizure control after reinstitution of their ASMs regimen. Pre-operative seizure frequency (p = 0.002) and occurrence of acute post-operative seizures (p = 0.01) were associated with increased risk for seizure recurrence post ASMs reduction. At the end of the observation period, 11% of patients were seizure free without drugs, 52% were seizure free with drugs and 37% still experienced seizures despite ASMs. Compared with pre-operative status, the number of ASMs was reduced in 41% of patients, unchanged in 55% of them and increased in only 4% of them. Successful MRg-LITT for ETLE allows for ASMs reduction in a significant portion of patients and complete ASMs withdrawal in a subset of them. Patients with higher pre-operative seizure frequency or occurrence of acute post operative seizures exhibit higher chances relapse post ASMs reduction. [ABSTRACT FROM AUTHOR]

Direct electrical stimulation of the amygdala can enhance declarative memory for specific events. An unanswered question is what underlying neurophysiological changes are induced by amygdala stimulation. To leverage interpretable machine learning to identify the neurophysiological processes underlying amygdala-mediated memory, and to develop more efficient neuromodulation technologies. Patients with treatment-resistant epilepsy and depth electrodes placed in the hippocampus and amygdala performed a recognition memory task for neutral images of objects. During the encoding phase, 160 images were shown to patients. Half of the images were followed by brief low-amplitude amygdala stimulation. For local field potentials (LFPs) recorded from key medial temporal lobe structures, feature vectors were calculated by taking the average spectral power in canonical frequency bands, before and after stimulation, to train a logistic regression classification model with elastic net regularization to differentiate brain states. Classifying the neural states at the time of encoding based on images subsequently remembered versus not-remembered showed that theta and slow-gamma power in the hippocampus were the most important features predicting subsequent memory performance. Classifying the post-image neural states at the time of encoding based on stimulated versus unstimulated trials showed that amygdala stimulation led to increased gamma power in the hippocampus. Amygdala stimulation induced pro-memory states in the hippocampus to enhance subsequent memory performance. Interpretable machine learning provides an effective tool for investigating the neurophysiological effects of brain stimulation. • Machine learning classification models can predict memory performance based on the CA1 Local Field Potential (LFP) states. • Machine learning classification models can reliably discriminate between stimulated and unstimulated neural states. • An increase in the CA1 LFP slow-gamma power during the encoding phase is predictive of subsequent memory performance. • Direct electrical stimulation of the basolateral amygdala can enhance the CA1 gamma oscillation. • Interpretable machine learning can be used for identifying the neurophysiological effects of brain stimulation. [ABSTRACT FROM AUTHOR]

Subthalamic deep brain stimulation (DBS) is an effective surgical treatment for Parkinson's disease and continues to advance technologically with an enormous parameter space. As such, in-silico DBS modeling systems have become common tools for research and development, but their underlying methods have yet to be standardized and validated. Evaluate the accuracy of patient-specific estimates of neural pathway activations in the subthalamic region against intracranial, cortical evoked potential (EP) recordings. Pathway activations were modeled in eleven patients using the latest advances in connectomic modeling of subthalamic DBS, focusing on the hyperdirect pathway (HDP) and corticospinal/bulbar tract (CSBT) for their relevance in human research studies. Correlations between pathway activations and respective EP amplitudes were quantified. Good model performance required accurate lead localization and image fusions, as well as appropriate selection of fiber diameter in the biophysical model. While optimal model parameters varied across patients, good performance could be achieved using a global set of parameters that explained 60% and 73% of electrophysiologic activations of CSBT and HDP, respectively. Moreover, restricted models fit to only EP amplitudes of eight standard (monopolar and bipolar) electrode configurations were able to extrapolate variation in EP amplitudes across other directional electrode configurations and stimulation parameters, with no significant reduction in model performance across the cohort. Our findings demonstrate that connectomic models of DBS with sufficient anatomical and electrical details can predict recruitment dynamics of white matter. These results will help to define connectomic modeling standards for preoperative surgical targeting and postoperative patient programming applications. • First evaluation of connectomic model estimates against cortical recordings in humans. • Lead localization and pathway excitability are crucial determinates of model accuracy. • Model accuracy is superior for omnidirectional compared to directional stimulation. • Patient-specificity is important for good model performance. • General model parameters may be suitable for predicting activations across patients. [ABSTRACT FROM AUTHOR]

Narcolepsy type 1 (NT1, narcolepsy with cataplexy) is a disabling neurological disorder caused by loss of excitatory orexin neurons from the hypothalamus and is characterized by decreased motivation, sleep-wake fragmentation, intrusion of rapid-eye-movement sleep (REMS) during wake, and abrupt loss of muscle tone, called cataplexy, in response to sudden emotions. We investigated whether subcortical stimulation, analogous to clinical deep brain stimulation (DBS), would ameliorate NT1 using a validated transgenic mouse model with postnatal orexin neuron degeneration. Using implanted electrodes in freely behaving mice, the immediate and prolonged effects of DBS were determined upon behavior using continuous video-electroencephalogram-electromyogram (video/EEG/EMG) and locomotor activity, and neural activation in brain sections, using immunohistochemical labeling of the immediate early gene product c-Fos. Brief 10-s stimulation to the region of the lateral hypothalamus and zona incerta (LH/ZI) dose-responsively reversed established sleep and cataplexy episodes without negative sequelae. Continuous 3-h stimulation increased ambulation, improved sleep-wake consolidation, and ameliorated cataplexy. Brain c-Fos from mice sacrificed after 90 min of DBS revealed dose-responsive neural activation within wake-active nuclei of the basal forebrain, hypothalamus, thalamus, and ventral midbrain. Acute and continuous LH/ZI DBS enhanced behavioral state control in a mouse model of NT1, supporting the feasibility of clinical DBS for NT1 and other sleep-wake disorders. • Hypothalamic DBS dose-responsively reverses sleep and cataplexy in mouse narcolepsy. • Hypothalamic DBS consolidates wakefulness and ameliorates cataplexy in mouse narcolepsy. • DBS activates Fos expression in wake-active nuclei of the hypothalamus, thalamus, and brainstem. • Neuromodulation of sleep-wakefulness for a primary sleep disorder appears feasible. [ABSTRACT FROM AUTHOR]

Recognizing familiar faces and learning new faces play an important role in social cognition. However, the underlying neural computational mechanisms remain unclear. Here, we record from single neurons in the human amygdala and hippocampus and find a greater neuronal representational distance between pairs of familiar faces than unfamiliar faces, suggesting that neural representations for familiar faces are more distinct. Representational distance increases with exposures to the same identity, suggesting that neural face representations are sharpened with learning and familiarization. Furthermore, representational distance is positively correlated with visual dissimilarity between faces, and exposure to visually similar faces increases representational distance, thus sharpening neural representations. Finally, we construct a computational model that demonstrates an increase in the representational distance of artificial units with training. Together, our results suggest that the neuronal population geometry, quantified by the representational distance, encodes face familiarity, similarity, and learning, forming the basis of face recognition and memory. [Display omitted] • Greater neuronal representational distance between familiar than unfamiliar faces • Neuronal representational distance increases with face learning and familiarization • Representational distance correlates with visual dissimilarity between faces • Exposure to visually similar faces increases neuronal representational distance Cao et al. show that the neuronal population geometry in the human amygdala and hippocampus, quantified by the representational distance, encodes face familiarity, similarity, and learning. The neuronal representational distance can be a generic code to explain neural face representations. [ABSTRACT FROM AUTHOR]

A study of orexin knockout mice reveals a phenotype that has a striking resemblance to humans suffering from narcolepsy. They also exhibit similarities with canarc-1 mutant dogs, narcolepsy's only known monogenic model. The findings, which also include the activation of orexin-containing neuron with the use of modafinil, provide evidence of orexin's function in the regulation of the state of wakefulness and sleep and provides a useful model for human narcolepsy.

Summary: The hypothalamic orexin neuropeptide acutely promotes appetite, yet orexin deficiency in humans and mice is associated with obesity. Prolonged effects of increased orexin signaling upon energy homeostasis have not been fully characterized. Here, we examine the metabolic effects of orexin gain of function utilizing genetic and pharmacologic techniques in mice. Transgenic orexin overexpression confers resistance to high-fat diet-induced obesity and insulin insensitivity by promoting energy expenditure and reducing consumption. Genetic studies indicate that orexin receptor-2 (OX2R), rather than OX1R signaling, predominantly mediates this phenotype. Likewise, prolonged central administration of an OX2R-selective peptide agonist inhibits diet-induced obesity. While orexin overexpression enhances the anorectic-catabolic effects of central leptin administration, obese leptin-deficient mice are completely resistant to the metabolic effects of orexin overexpression or OX2R agonist infusion. We conclude that enhanced orexin-OX2R signaling confers resistance to diet-induced features of the metabolic syndrome through negative energy homeostasis and improved leptin sensitivity. [Copyright &y& Elsevier]

Background Several case reports and small series have indicated that tardive dystonia is responsive to globus pallidus deep brain stimulation. Whether different subtypes or distributions of tardive dystonia are associated with different outcomes remains unknown. Methods We assessed the outcomes and temporal profile of improvement of eight tardive dystonia patients who underwent globus pallidus deep brain stimulation over the past six years through record review. Due to the retrospective nature of this study, it was not blinded or placebo controlled. Results Consistent with previous studies, deep brain stimulation improved the overall the Burke–Fahn–Marsden motor scores by 85.1 ± 13.5%. The distributions with best responses in descending order were upper face, lower face, larynx/pharynx, limbs, trunk, and neck. Patients with prominent cervical dystonia demonstrated improvement in the Toronto Western Spasmodic Torticollis Rating Scale but improvements took several months. In four patients the effects of deep brain stimulation on improvement in Burke Fahn Marsden score was rapid, while in four cases there was partial rapid response of neck and trunk dystonia followed by was gradual resolution of residual symptoms over 48 months. Conclusion Our retrospective analysis shows excellent resolution of tardive dystonia after globus pallidus deep brain stimulation. We found instantaneous response, except with neck and trunk dystonia where partial recovery was followed by further resolution at slower rate. Such outcome is encouraging for using deep brain stimulation in treatment of tardive dystonia. [ABSTRACT FROM AUTHOR]

The amygdala is a key structure mediating emotional processing. Few studies have used direct electrical stimulation of the amygdala in humans to examine stimulation-elicited physiological and emotional responses, and the nature of such effects remains unclear. Determining the effects of electrical stimulation of the amygdala has important theoretical implications for current discrete and dimensional neurobiological theories of emotion, which differ substantially in their predictions about the emotional effects of such stimulation. To examine the effects of amygdala stimulation on physiological and subjective emotional responses we examined epilepsy patients undergoing intracranial EEG monitoring in which depth electrodes were implanted unilaterally or bilaterally in the amygdala. Nine subjects underwent both sham and acute monopolar electrical stimulation at various parameters in electrode contacts located in amygdala and within lateral temporal cortex control locations. Stimulation was applied at either 50 Hz or 130 Hz, while amplitudes were increased stepwise from 1 to 12 V, with subjects blinded to stimulation condition. Electrodermal activity (EDA), heart rate (HR), and respiratory rate (RR) were simultaneously recorded and subjective emotional response was probed after each stimulation period. Amygdala stimulation (but not lateral control or sham stimulation) elicited immediate and substantial dose-dependent increases in EDA and decelerations of HR, generally without affecting RR. Stimulation elicited subjective emotional responses only rarely, and did not elicit clinical seizures in any subject. These physiological results parallel stimulation findings with animals and are consistent with orienting/defensive responses observed with aversive visual stimuli in humans. In summary, these findings suggest that acute amygdala stimulation in humans can be safe and can reliably elicit changes in emotion physiology without significantly affecting subjective emotional experience, providing a useful approach for investigation of amygdala-mediated modulatory effects on cognition. • Increasing amplitudes of amygdala stimulation elicited dose-dependent increases in EDA and decreases in heart rate. • In one patient, amygdala stimulation caused subjective experiences of fear and anxiety, accompanied by increased heart rate. • Amygdala stimulation reliably elicits changes in autonomic activity in a dose-dependent and safe manner. • At the amplitudes of stimulation delivered, amygdala stimulation elicits subjective emotional experiences only infrequently. [ABSTRACT FROM AUTHOR]