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Plus généralement utilisée pour l'étude des phases fluides, la spectrophotométrie d'absorption infrarouge a trouvé un important champ d'application dans l'analyse minéralogique quantitative globale des roches sédimentaires. En s'appuyant sur deux exemples précis de constituants importants des sédiments (quartz et calcite), on montre ici les différentes possibilités analytiques avec échantillon seul, compensation du diluant pur, compensation d'un minéral pur et compensation d'un minéral en mélange artificiel et naturel (roche sédimentaire). On décrit les modifications subies par les spectres et des courbes d'étalonnages sont dressées dans chaque cas. Les données recueillies permettent de vérifier l'utilisation légitime de la loi d'absorption pour ces analyses infrarouges de phases solides impliquant une compensation, et donc un traitement des spectres originaux, l'erreur relative maximale expérimentale ne dépassant pas quelques pourcents dans les cas les plus défavorables. Dans les limites du dosage de minéraux à composition chimique et structure cristalline fixes, l'analyse d'un minéral par sa compensation partielle peut être d'un grand intérêt pour des constituants majeurs de roches, car autorisant l'analyse là où une concentration trop élevée l'aurait interdite. Cette méthode de compensation est plus délicate, voire impossible, pour les solutions solides ou tout minéral à formule chimique variable. D'une manière générale, les principaux constituants des roches sédimentaires peuvent être ainsi quantifiés sur un seul spectre par l'analyse IR qui offre donc la possibilité d'une définition numérique des faciès. Although it is more generally used for analyzing fluid phases, infrared absorption spectrophotometry has found an important area of application in the bulk quantitative mineralogical analysis of sedimentary rocks. On the basis of two specific examples of important constituents of sediments (quartz and calcite), this article shows the different analytical possibilities with a sample alone, with compensation for a pure diluent, with compensation for a single mineral and with compensation for a mineral in an artificial and a natural mixture (sedimentary rock). The changes undergone by the spectra are described, and calibration curves are plotted in each case. The data gathered are used to check the justified use of the absorption law for these solid-phase infrared analysis, involving a compensation, and hence the processing of the original spectra, with the maximum relative experimental error being no more than several percent in the most unfavorable cases. Within the limits of the detection of minerals having a set chemical composition and crystalline structure, the analysis of a mineral by its partial compensation may be of great importance for the major constituents of rocks because it enables analysis to be performed where too high a concentration would have made such analysis impossible heretofore. This compensation method is more delicate or even impossible for solid solutions or for any mineral with a variable chemical formula. Generaly speaking, the main constituents of sedimentary rocks can thus be quantified from a single spectrum by IR analysis which thus makes it possible to obtain a numerical definition of facies.

The role of opal deposits in the cells surrounding oocytes and cells of interstitial tissues in the ovary of the ascidian Styela clava was examined. Cytological analysis of the ovarian cells showed granular inclusions embedded in the acid mucopolysaccharides. Since the siliceous deposits were found only in the maturing ovaries, the bioaccumulation was linked to reproductive functions.

Julianna H Prim,1–3,* Sangtae Ahn,1,2,* Maria I Davila,1 Morgan L Alexander,1,2 Karen L McCulloch,3,4,* Flavio Fröhlich1,2,5–8,* 1Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; 2Carolina Center for Neurostimulation, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; 3Department of Allied Health Sciences, Human Movement Science Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; 4Division of Physical Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; 5Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; 6Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; 7Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; 8Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA*These authors contributed equally to this workCorrespondence: Flavio FröhlichUniversity of North Carolina at Chapel Hill 116 Manning Dr, Mary Ellen Jones Building 6018, Chapel Hill, NC 27599, USATel +1 919 966 4584Email flavio_frohlich@med.unc.eduBackground: Chronic low back pain (CLBP) is characterized by an alteration in pain processing by the central nervous system that may affect autonomic nervous system (ANS) balance. Heart rate variability (HRV) reflects the balance of parasympathetic and sympathetic ANS activation. In particular, respiratory sinus arrhythmia (RSA) solely reflects parasympathetic input and is reduced in CLBP patients. Yet, it remains unknown if non-invasive brain stimulation can alter ANS balance in CLBP patients.Objective: To evaluate if non-invasive brain stimulation modulates the ANS, we analyzed HRV metrics collected in a previously published study of transcranial alternating current stimulation (tACS) for the modulation of CLBP through enhancing alpha oscillations. We hypothesized that tACS would increase RSA.Methods: A randomized, crossover, double-blind, sham-controlled pilot study was conducted to investigate the effects of 10Hz-tACS on metrics of ANS balance calculated from electrocardiogram (ECG). ECG data were collected for 2 mins before and after 40 mins of 10Hz-tACS or sham stimulation.Results: There were no significant changes in RSA or other frequency-domain HRV components from 10Hz-tACS. However, exploratory time-domain HRV analyses revealed a significant increase in the standard deviation of normal intervals between R-peaks (SDNN), a measure of ANS balance, for 10Hz-tACS relative to sham.Conclusion: Although tACS did not significantly increase RSA, we found in an exploratory analysis that tACS modulated an integrated HRV measure of both ANS branches. These findings support the further study of how the ANS and alpha oscillations interact and are modulated by tACS.ClinicalTrials.gov: Transcranial Alternating Current Stimulation in Back Pain – Pilot Study, NCT03243084.Keywords: low back pain, autonomic nervous system, heart rate variability, transcranial alternating current stimulation

Competing Interests: Dr. Townsend is an employee and shareholder of EPI and an employee of Pulvinar Neuro and receives funding from the NIH. Dr. Walker is an employee of Pulvinar Neuro. Dr. Rubinow receives research funding from the NIH, the Baszucki Foundation, and Sage Therapeutics; serves on the scientific advisory boards of Sage Therapeutics, Sensorium Therapeutics, and the Foundation of Hope; serves on the clinical advisory boards of Felicitypharma and Embarkneuro; is a consultant to Brii Biosciences, GH Research-Ireland, and Aldeyra Therapeutics; has stock options from Sensorium Therapeutics and Sage Therapeutics. Dr. Frohlich is a shareholder of EPI and receives payments from EPI for chairing the scientific advisory board, and is listed as an inventor on patents issued to UNC-CHapel Hill on non-invasive brain stimulation. The other authors report no financial relationships with commercial interests.

Mild Cognitive Impairment (MCI) is a neurological disorder at the transition between normal cognitive decline and dementia. Despite the potential role of neuroinflammation in the pathogenesis of MCI, infectious triggers remain mostly unknown. Infection with Bartonella spp., a zoonotic bacterium, has recently been associated with diffuse neurological and psychiatric symptoms. Given the preferential endothelial localization of Bartonella spp. and the role of vascular changes in neurocognitive decline, we hypothesized that there is an association between Bartonella spp. infection and pathologically accelerated decline in cognitive function in aging. To test this hypothesis, we collected serological and molecular markers of past and present Bartonella spp. infection in a sample of older people with and without MCI. Samples were processed in a blinded way to exclude laboratory biases. Contrary to our hypothesis, people with MCI were not more likely than people without MCI to have an active Bartonella spp. infection as measured by droplet digital PCR (p = 0.735) and quantitative PCR (p = 1). In addition, there was no significant difference in positive serological results between cases and controls (p = 0.461). Overall, higher-than-expected active Bartonella spp. infection (37% by ddPCR) and seroreactivity (71% by indirect fluorescent antibody assay) were found in people without MCI. Conclusions require caution, as our study was limited by the small number of cases with MCI. Overall, our results identified a higher than previously recognized rate of exposure and infection with Bartonella spp. in this older study population but does not support a specific role for such infection in MCI., Competing Interests: In conjunction with Dr. S. Sontakke and North Carolina State University, E. B. Breitschwerdt holds US Patent No. 7,115,385 Media and Methods for Cultivation of Microorganisms, which was issued on October 3rd, 2006. He is a co-founder, shareholder and Chief Scientific Officer for Galaxy Diagnostics, a company that provides advanced diagnostic testing for the detection of Bartonella spp. infections. Dr. Ricardo Maggi is a co-founder and the Chief Technical Officer for Galaxy Diagnostics Inc. Drs Breitschwerdt and Maggi are full-time employees of North Carolina State University. Dr. Frohlich is a full-time employee of the University of North Carolina – Chapel Hill. Dr. Frohlich is the lead inventor of IP issued to UNC and licensed to: Electromedical Products International (EPI). In the last twelve months, Dr. Frohlich has received consulting honoraria from the following entities: EPI, Insel Spital, and the University of Michigan. Dr. Frohlich is a shareholder of EPI. In the last twelve months, Dr. Frohlich has received royalties from Academic Press and the University of North Carolina at Chapel Hill. Ms. Guirguis, Pupillo, and Rodrigues report no financial relationships with commercial interests. All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Guirguis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

There is a lack of consensus on anatomical nomenclature, standards of documentation, and functional equivalence of the frontal cortex between species. There remains a major gap between human prefrontal function and interpretation of findings in the mouse brain that appears to lack several key prefrontal areas involved in cognition and psychiatric illnesses. The ferret is an emerging model organism that has gained traction as an intermediate model species for the study of top-down cognitive control and other higher-order brain functions. However, this research has yet to benefit from synthesis. Here, we provide a summary of all published research pertaining to the frontal and/or prefrontal cortex of the ferret across research scales. The targeted location within the ferret brain is summarized visually for each experiment, and the anatomical terminology used at time of publishing is compared to what would be the appropriate term to use presently. By doing so, we hope to improve clarity in the interpretation of both previous and future publications on the comparative study of frontal cortex., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Control over internal representations requires the prioritization of relevant information and suppression of irrelevant information. The frontoparietal network exhibits prominent neural oscillations during these distinct cognitive processes. Yet, the causal role of this network-scale activity is unclear. Here, we targeted theta-frequency frontoparietal coherence and dynamic alpha oscillations in the posterior parietal cortex using online rhythmic transcranial magnetic stimulation (TMS) in women and men while they prioritized or suppressed internally maintained working memory (WM) representations. Using concurrent high-density EEG, we provided evidence that we acutely drove the targeted neural oscillation and TMS improved WM capacity only when the evoked activity corresponded with the desired cognitive process. To suppress an internal representation, we increased the amplitude of lateralized alpha oscillations in the posterior parietal cortex contralateral to the irrelevant visual field. For prioritization, we found that TMS to the prefrontal cortex increased theta-frequency connectivity in the prefrontoparietal network contralateral to the relevant visual field. To understand the spatial specificity of these effects, we administered the WM task to participants with implanted electrodes. We found that theta connectivity during prioritization was directed from the lateral prefrontal to the superior posterior parietal cortex. Together, these findings provide causal evidence in support of a model where a frontoparietal theta network prioritizes internally maintained representations and alpha oscillations in the posterior parietal cortex suppress irrelevant representations., (Copyright © 2024 the authors.)

Sustained visual attention allows us to process and react to unpredictable, behaviorally relevant sensory input. Sustained attention engages communication between the higher-order visual thalamus and its connected cortical regions. However, it remains unclear whether there is a causal relationship between oscillatory circuit dynamics and attentional behavior in these thalamo-cortical circuits. By using rhythmic optogenetic stimulation in the ferret, we provide causal evidence that higher-order visual thalamus coordinates thalamo-cortical and cortico-cortical functional connectivity during sustained attention via spike-field phase locking. Increasing theta but not alpha power in the thalamus improved accuracy and reduced omission rates in a sustained attention task. Further, the enhancement of effective connectivity by stimulation was correlated with improved behavioral performance. Our work demonstrates a potential circuit-level causal mechanism for how the higher-order visual thalamus modulates cortical communication through rhythmic synchronization during sustained attention., Competing Interests: Declaration of interests F.F. is the lead inventor of intellectual property filed on the topics of noninvasive brain stimulation by the University of North Carolina. F.F. serves as a paid consultant to Electromedical Products International. The work presented here is completely unrelated., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Preliminary studies suggest that infection with Bartonella bacteria can not only cause a characteristic rash, headache, fever, and fatigue but also neuropsychiatric symptoms. To date, this association has only been reported in case studies, and it remains unclear if this association generalizes to larger samples., Methods: We used Amazon's Mechanical Turk (MTurk) to crowdsource a large sample (N = 996) of individuals to ascertain the extent to which the presence of participant-identified Bartonella-associated cutaneous lesions (BACL) was associated with self-reported measures of anxiety, depression, and schizotypy. Participants were asked to select images of cutaneous lesions they had seen on their own bodies and complete a battery of self-report questionnaires to assess psychiatric symptoms. Participants were not informed that the focus of the study was on potential dermatological lesions associated with Bartonella. Point-biserial correlations were used to determine the potential relationship between selecting a BACL image and the severity of self-reported psychiatric symptoms., Results: Scores of anxiety, depression, and schizotypy were positively and significantly correlated with selecting a BACL image. Furthermore, self-report scores of 10 or higher on the GAD-7 and PHQ-9, which represent the suggested clinical cutoffs for meeting criteria for a depressive or anxiety-related disorder, were also significantly associated with selecting a BACL image. Non-Bartonella-associated cutaneous legions were also significantly associated with self-reported measures of psychiatric symptoms., Discussion: The current study broadens the link between the presence of BACL and the presence of psychiatric symptoms of anxiety, depression, and schizotypy and extends a potential relationship beyond the small sample sizes of previous case studies and case series. Further investigation is recommended to address limitations and expand on these findings., Competing Interests: FF is a full-time employee of the University of North Carolina—Chapel Hill. FF is the lead inventor of IP issued to UNC and licensed to Electromedical Products International (EPI). In the last 12 months, FF has received consulting honoraria from the following entities: EPI, Insel Spital, and the University of Michigan. In the last 12 months, FF has received royalties from Academic Press and the University of North Carolina at Chapel Hill. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Stewart, Korsapathy and Frohlich.)

Attention deficits are common in psychiatric and neurological disorders. The transdiagnostic nature of impaired attention suggests a common set of underlying neural circuits. Yet, there are no circuit-based treatments such as non-invasive brain stimulation currently available due to the lack of sufficiently delineated network targets. Therefore, to better treat attentional deficits, a comprehensive functional dissection of neural circuits underlying attention is imperative. This can be achieved by taking advantage of preclinical animal models and well-designed behavioral assays of attention. The resulting findings in turn can be translated to the development of novel interventions with the goal of advancing them to clinical practice. Here we show that the five-choice serial reaction time task has greatly facilitated the study of the neural circuits underlying attention in a well-controlled setting. We first introduce the task and then focus on its application in preclinical studies on sustained attention, especially in the context of state-of-the-art neuronal perturbations., Competing Interests: Declaration of Competing Interest F.F. is the lead inventor of IP filed on the topics of noninvasive brain stimulation by UNC and receives royalty payments. F.F. has received consulting honoraria and royalties from the following entities in the last twelve months: EPI, Academic Press, Insel Spital, and University of Michigan. Q.F. declares no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The Research Domain Criteria (RDoC) initiative challenges researchers to build neurobehavioral models of psychiatric illness with the hope that such models identify better targets that will yield more effective treatment. However, a guide for building such models was not provided and symptom heterogeneity within Diagnostic Statistical Manual categories has hampered progress in identifying endophenotypes that underlie mental illness. We propose that the best chance to discover viable biomarkers and treatment targets for psychiatric illness is to investigate a triangle of relationships: severity of a specific psychiatric symptom that correlates to mental activity that correlates to a neural activity signature. We propose that this is the minimal model complexity required to advance the field of psychiatry. With an understanding of how neural activity relates to the experience of the patient, a genuine understanding for how treatment imparts its therapeutic effect is possible. After the discovery of this three-fold relationship, causal testing is required in which the neural activity pattern is directly enhanced or suppressed to provide causal, instead of just correlational, evidence for the biomarker. We suggest using non-invasive brain stimulation (NIBS) as these techniques provide tools to precisely manipulate spatial and temporal activity patterns. We detail how this approach enabled the discovery of two orthogonal electroencephalography (EEG) activity patterns associated with anhedonia and anxiosomatic symptoms in depression that can serve as future treatment targets. Altogether, we propose a systematic approach for building neurobehavioral models for dimensional psychiatry.

The individual alpha frequency (IAF) has previously been identified as a unique neural signature within the 8-12 Hz alpha frequency band. However, the day-to-day variability of this feature is unknown. To investigate this, healthy participants recorded their own brain activity daily at home using the Muse 2 headband, a low-cost consumer-grade mobile electroencephalography (EEG) device. Resting-state recordings of all participants using a high-density (HD) EEG were also collected in lab before and after the at-home data collection period. We found that the IAF extracted from the Muse 2 was comparable to that of location-matched HD-EEG electrodes. No significant difference was found between these IAF values before and after the at-home recording period for the HD-EEG device. Similarly, there was also no statistically significant difference between the beginning and end of the at-home recording period for the Muse 2 headband over 1 month. Despite the group-level stability of IAF, the individual-level day-to-day IAF variability carried mental health-relevant information: Exploratory analyses revealed a relationship between IAF day-to-day variability and trait anxiety. We also noted that the IAF systematically varied across the scalp and although the Muse 2 electrodes do not cover the occipital lobe where alpha oscillations were the strongest, IAFs measured in the temporal lobe and occipital lobe were strongly correlated. Altogether, these results show that mobile EEG devices are useful for studying IAF variability. The relationship between day-to-day variability of region-specific IAF and the dynamics of psychiatric symptoms, particularly anxiety, should be further investigated., (© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

People with schizophrenia exhibit reduced alpha oscillations and frontotemporal coordination of brain activity. Alpha oscillations are associated with top-down inhibition. Reduced alpha oscillations may fail to censor spurious endogenous activity, leading to auditory hallucinations. Transcranial alternating current stimulation (tACS) at the alpha frequency was shown to enhance alpha oscillations in people with schizophrenia and may thus be a network-based treatment for auditory hallucinations. We conducted a double-blind, randomized, placebo-controlled pilot clinical trial to examine the efficacy of 10-Hz tACS in treating auditory hallucinations in people with schizophrenia. 10-Hz tACS was administered in phase at the dorsolateral prefrontal cortex and the temporoparietal junction with a return current at Cz. Patients were randomized to receive tACS or sham for five consecutive days during the treatment week (40 min/day), followed by a maintenance period, during which participants received weekly tACS (40 min/visit) or sham. tACS treatment reduced general psychopathology (p < 0.05, Cohen's d = -0.690), especially depression (p < 0.005, Cohen's d = -0.806), but not auditory hallucinations. tACS treatment increased alpha power in the target region (p < 0.05), increased the frequency of peak global functional connectivity towards 10 Hz (p < 0.05), and reduced left-right frontal functional connectivity (p < 0.005). Importantly, changes in brain functional connectivity significantly correlated with symptom improvement (p < 0.05). Daily 10 Hz-tACS increased alpha power and altered alpha-band functional connectivity. Successful target engagement reduced depression and other general psychopathology symptoms, but not auditory hallucinations. Considering existing research of 10Hz tACS as a treatment for major depressive disorder, our study demonstrates its transdiagnostic potential for treating depression., (© 2022. The Author(s).)

Objective: Although relatively costly and non-scalable, non-invasive neuromodulation interventions are treatment alternatives for neuropsychiatric disorders. The recent developments of highly-deployable transcranial electric stimulation (tES) systems, combined with mobile-Health technologies, could be incorporated in digital trials to overcome methodological barriers and increase equity of access. The study aims are to discuss the implementation of tES digital trials by performing a systematic scoping review and strategic process mapping, evaluate methodological aspects of tES digital trial designs, and provide Delphi-based recommendations for implementing digital trials using tES., Methods: We convened 61 highly-productive specialists and contacted 8 tES companies to assess 71 issues related to tES digitalization readiness, and processes, barriers, advantages, and opportunities for implementing tES digital trials. Delphi-based recommendations (>60% agreement) were provided., Results: The main strengths/opportunities of tES were: (i) non-pharmacological nature (92% of agreement), safety of these techniques (80%), affordability (88%), and potential scalability (78%). As for weaknesses/threats, we listed insufficient supervision (76%) and unclear regulatory status (69%). Many issues related to methodological biases did not reach consensus. Device appraisal showed moderate digitalization readiness, with high safety and potential for trial implementation, but low connectivity., Conclusions: Panelists recognized the potential of tES for scalability, generalizability, and leverage of digital trials processes; with no consensus about aspects regarding methodological biases., Significance: We further propose and discuss a conceptual framework for exploiting shared aspects between mobile-Health tES technologies with digital trials methodology to drive future efforts for digitizing tES trials., (Copyright © 2022 International Federation of Clinical Neurophysiology. All rights reserved.)

Prefrontal cortex exerts control over sensory and motor systems via cross-frequency coupling. However, it is unknown whether these signals play a role in reward-based decision-making and whether such dynamic network configuration is altered in a major depressive episode. We recruited men and women with and without depression to perform a streamlined version of the Expenditure of Effort for Reward Task during recording of electroencephalography. Goal-directed behavior was quantified as willingness to exert physical effort to obtain reward, and reward-evaluation was the degree to which the decision to exert effort was modulated by incentive level. We found that the amplitude of frontal-midline theta oscillations was greatest in participants with the greatest reward-evaluation. Furthermore, coupling between frontal theta phase and parieto-occipital gamma amplitude was positively correlated with reward-evaluation. In addition, goal-directed behavior was positively correlated with coupling between frontal delta phase to motor beta amplitude. Finally, we performed a factor analysis to derive 2 symptom dimensions and found that mood symptoms positively tracked with reward-evaluation and motivation symptoms negatively tracked with goal-directed behavior. Altogether, these results provide evidence that 2 aspects of reward-based decision-making are instantiated by different modes of prefrontal top-down control and are modulated in different symptom dimensions of depression., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Alpha oscillations have been proposed to provide phasic inhibition in the brain. Yet, pinging alpha oscillations with transcranial magnetic stimulation (TMS) to examine phase-dependent network excitability has resulted in conflicting findings. At the cellular level, such gating by the alpha oscillation remains poorly understood., Objective: We examine how the excitability of pyramidal cells and presumed fast-spiking inhibitory interneurons depends on the phase of the alpha oscillation., Methods: Optogenetic stimulation pulses were administered at random phases of the alpha oscillation in the posterior parietal cortex (PPC) of two adult ferrets that expressed channelrhodopsin in pyramidal cells. Post-stimulation firing probability was calculated as a function of the stimulation phase of the alpha oscillation for both verum and sham stimulation., Results: The excitability of pyramidal cells depended on the alpha phase, in anticorrelation with their intrinsic phase preference; pyramidal cells were more responsive to optogenetic stimulation at the alpha phase with intrinsically low firing rates. In contrast, presumed fast-spiking inhibitory interneurons did not show such a phase dependency despite their stronger intrinsic phase preference., Conclusions: Alpha oscillations gate input to PPC in a phase-dependent manner such that low intrinsic activity was associated with higher responsiveness to input. This finding supports a model of cortical oscillation, in which internal processing and communication are limited to the depolarized half-cycle, whereas the other half-cycle serves as a signal detector for unexpected input. The functional role of different parts of the alpha cycle may vary across the cortex depending on local neuronal firing properties., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: F.F. is the lead inventor of IP filed on the topics of noninvasive brain stimulation by UNC. F.F. is the founder and CSO of Pulvinar Neuro LLC. He owns shares in Pulvinar Neuro. The company played no role in this research. FF has received honoraria from the following entities in the last twelve months: Sage Therapeutics, Academic Press, Insel Spital, and Strategic Innovation. M.Z. declares no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Left frontal alpha oscillations are associated with decreased approach motivation and have been proposed as a target for noninvasive brain stimulation for the treatment of depression and anhedonia. Indeed, transcranial alternating current stimulation (tACS) at the alpha frequency reduced left frontal alpha power and was associated with a higher response rate than placebo stimulation in patients with major depressive disorder (MDD) in a recent double-blind, placebo-controlled clinical trial., Methods: In this current study, we aimed to replicate successful target engagement by delineating the effects of a single session of bifrontal tACS at the individualized alpha frequency (IAF-tACS) on alpha oscillations in patients with MDD. Eighty-four participants were randomized to receive verum or sham IAF-tACS. Electrical brain activity was recorded during rest and while viewing emotionally salient images before and after stimulation to investigate whether the modulation of alpha oscillation by tACS exhibited specificity with regard to valence., Results: In agreement with the previous study of tACS in MDD, we found that a single session of bifrontal IAF-tACS reduced left frontal alpha power during the resting state when compared with placebo. Furthermore, the reduction of left frontal alpha oscillation by tACS was specific for stimuli with positive valence. In contrast, these effects on left frontal alpha power were not found in healthy control participants., Conclusions: Together, these results support an important role of tACS in reducing left frontal alpha oscillations as a future treatment for MDD., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Autonomic dysfunction and depression are common non-motor symptoms of Parkinson's disease (PD) that confer poorer prognosis. These PD symptoms may have overlapping pathophysiologic underpinnings., Objective: To investigate associations between autonomic and depression symptoms in early PD, and their evolution over time., Methods: We obtained data from the Parkinson's Progression Markers Initiative, a prospective open-access database of early PD. Regression analyses were used to model effects of depression on autonomic symptoms in controls and in PD at baseline, visit 6 (24 months after baseline), and visit 12 (60 months after baseline), correcting for multiple comparisons., Results: Data from 421 people with PD at baseline, 360 at visit 6, 300 at visit 12, and 193 controls were included. When controlling for age, depression, and anti-hypertensive medications, depression predicted autonomic symptoms in all groups. Accounting for motor symptoms did not alter these associations. When comparing groups, the influence of depression on autonomic symptoms was stronger in all PD groups compared to controls, and strongest in PD at visit 12. Depression predicted the presence of orthostatic hypotension only in the PD group at visit 12., Conclusion: We demonstrated the important impact of depression on autonomic symptoms in early and middle stages of PD, which are independent of motor symptoms. Though the physiologic basis of these two PD symptoms are not fully understood, our findings add to pathologic evidence of a shared mechanistic substrate, separate from that responsible for PD motor symptoms. These findings may influence clinical management and development of novel therapies.

Frontal-midline theta (FMT) oscillations are increased in amplitude during cognitive control tasks. Since these tasks often conflate cognitive control and cognitive effort, it remains unknown if FMT amplitude maps onto cognitive control or effort. To address this gap, we utilized the glucose facilitation effect to manipulate cognitive effort without changing cognitive control demands. We performed a single-blind, crossover human study in which we provided participants with a glucose drink (control session: volume-matched water) to reduce cognitive effort and improve performance on a visuospatial working memory task. Following glucose consumption, participants performed the working memory task at multiple time points of a 3-h window to sample across the rise and fall of blood glucose. Using high-density electroencephalography (EEG), we calculated FMT amplitude during the delay period of the working memory task. Source localization analysis revealed that FMT oscillations originated from bilateral prefrontal cortex. We found that glucose increased working memory accuracy during the high working memory load condition but decreased FMT amplitude. The decrease in FMT amplitude coincided with both peak blood glucose elevation and peak performance enhancement for glucose relative to water. Therefore, the positive association between glucose consumption and task performance provided causal evidence that the amplitude of FMT oscillations may correspond to cognitive effort, rather than cognitive control. Due to the COVID-19 pandemic, data collection was terminated prematurely; the preliminary nature of these findings due to small sample size should be contextualized by rigorous experimental design and use of a novel causal perturbation to dissociate cognitive effort and cognitive control. NEW & NOTEWORTHY We investigated whether frontal-midline theta (FMT) oscillations tracked with cognitive control or cognitive effort by simultaneous manipulation of cognitive control demands in a working memory task and causal perturbation of cognitive effort using glucose consumption. Facilitation of performance from glucose consumption corresponded with decreased FMT amplitude, which provided preliminary causal evidence for a relationship between FMT amplitude with cognitive effort.

Neural oscillations at the network level synchronize activity between regions and temporal scales. Transcranial alternating current stimulation (tACS), the delivery of low-amplitude electric current to the scalp, provides a tool for investigating the causal role of neural oscillations in cognition. The parameter space for tACS is vast and optimization is required in terms of temporal and spatial targeting. We review emerging techniques and suggest novel approaches that capitalize on the non-sinusoidal and transient nature of neural oscillations and leverage the flexibility provided by a customizable electrode montage and electrical waveform. The customizability and safety profile of tACS make it a promising tool for precision intervention in psychiatric illnesses., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Competing Interests: Conflict of interest: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: F.F. is the lead inventor of Intellectual property filed by University of North Carolina. F.F. is the founder, Chief Science Officer and majority owner of Pulvinar Neuro LLC. J.R., G.U. and F.L. have no conflicts to declare.

Cognitive control is the capacity to guide motor and perceptual systems towards abstract goals. High-frequency neural oscillations related to motor activity in the beta band (13-30 Hz) and to visual processing in the gamma band (>30 Hz) are known to be modulated by cognitive control signals. One proposed mechanism for cognitive control is via cross-frequency coupling whereby low frequency network oscillations in prefrontal cortex (delta from 2-3 Hz and theta from 4-8 Hz) guide the expression of motor-related activity in action planning and guide perception-related activity in memory access. However, there is no causal evidence for cross-frequency coupling in these dissociable components of cognitive control. To address this important gap in knowledge, we delivered cross-frequency transcranial alternating current stimulation (CF-tACS) during performance of a task that manipulated cognitive control demands along two dimensions: the abstraction of the rules of the task (nested levels of action selection) that increased delta-beta coupling and the number of rules (set-size held in memory) that increased theta-gamma coupling. As hypothesized, we found that CF-tACS increased the targeted phase-amplitude coupling and modulated task performance of the associated cognitive control component. These findings provide causal evidence that prefrontal cortex orchestrates different components of cognitive control via two different cross-frequency coupling modalities., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Recently, infections with emerging zoonotic bacteria of the genus Bartonella have been reported in association with a range of central nervous system (CNS) symptoms. Currently, it remains unknown if Bartonella spp. infection is associated with symptoms of schizophrenia/schizoaffective disorder (SCZ/SAD). The objective of this study was to determine if there is an association between Bartonella species infection and SCZ/SAD. A secondary objective was to determine if SCZ/SAD symptoms were more severe among participants with documented Bartonella spp. infection. Using a case-control study design, 17 cases and 13 controls were evaluated with a series of clinical and cognitive assessments. Blood samples were collected and tested for Bartonella spp. infection using serological, microbiological, and molecular techniques. People with SCZ/SAD were more likely than healthy volunteers to have Bartonella spp. DNA in their bloodstream, with 11 of 17 cases (65%) positive by Bartonella spp. droplet digital PCR (ddPCR). In comparison, only one healthy volunteer was Bartonella spp. ddPCR positive (8%, p  = 0.0024). Based on serology, Bartonella spp. exposure was common among people with SCZ/SAD (12 of 17) as well as among healthy volunteers (12 of 13), with no significant difference between the groups ( p  = 0.196). Within the case group of people with SCZ/SAD, there was no significant difference in SCZ/SAD severity scores between people with and without ddPCR evidence of Bartonella spp. infection. This pilot study provides preliminary evidence in support of future investigations that should examine a potential contribution of Bartonella spp. infection to SCZ/SAD.

Background: To obtain desirable goals, individuals must predict the outcome of specific choices, use that information to direct appropriate actions, and adjust behavior accordingly in changing environments (behavioral flexibility). Substance use disorders are marked by impairments in behavioral flexibility along with decreased prefrontal cortical function that limits the efficacy of treatment strategies. Restoring prefrontal hypoactivity, ideally in a noninvasive manner, is an intriguing target for improving flexible behavior and treatment outcomes., Methods: A behavioral flexibility task was used in Long-Evans male rats (n = 97) in conjunction with electrophysiology, optogenetics, and a novel rat model of transcranial alternating current stimulation (tACS) to examine the prelimbic cortex (PrL) to nucleus accumbens (NAc) core circuit in behavioral flexibility and determine whether tACS can restore cocaine-induced neural and cognitive dysfunction., Results: Optogenetic inactivation revealed that the PrL-NAc core circuit is necessary for the ability to learn strategies to flexibly shift behavior. Cocaine self-administration history caused aberrant PrL-NAc core neural encoding and deficits in flexibility. Optogenetics that selectively activated the PrL-NAc core pathway prior to learning rescued cocaine-induced cognitive flexibility deficits. Remarkably, tACS prior to learning the task reestablished adaptive signaling in the PrL-NAc circuit and restored flexible behavior in a relatively noninvasive and frequency-specific manner., Conclusions: We establish a role of NAc core-projecting PrL neurons in behavioral flexibility and provide a novel noninvasive brain stimulation method in rats to rescue cocaine-induced frontal hypofunction and restore flexible behavior, supporting a role of tACS as a therapeutic to treat cognitive deficits in substance use disorders., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Many psychiatric and neurological illnesses can be conceptualized as oscillopathies defined as pathological changes in brain network oscillations. We previously proposed the application of rational design for the development of non-invasive brain stimulation for the modulation and restoration of cortical oscillations as a network therapeutic. Here, we show how transcranial alternating current stimulation (tACS), which applies a weak sine-wave electric current to the scalp, may serve as a therapeutic platform for the treatment of CNS illnesses. Recently, an initial series of double-blind, placebo-controlled treatment trials of tACS have been published. Here, we first map out the conceptual underpinnings of such trials with focus on target identification, engagement, and validation. Then, we discuss practical aspects that need to be considered for successful trial execution, with particular regards to ensuring successful study blind. Finally, we briefly review the few published double-blind tACS trials and conclude with a proposed roadmap to move the field forward with the goal of moving from pilot trials to convincing efficacy studies of tACS.

Asymmetrical expression of alpha oscillations in the frontal cortex, increased left relative to right, is a phenotype associated with increased behavioral inhibition and mood-related psychiatric illnesses. However, investigations of frontal alpha asymmetry in mood-disorders have yielded inconsistent findings. A better understanding of factors that contribute to individual differences is required to establish a useful biomarker for the diagnosis and treatment of mood and stress related disorders. A novel factor is hormone concentration, as steroid hormones play a prominent role in regulating mood and stress. To investigate this question, concentrations of testosterone and estradiol were sampled. Multiple linear regression revealed that low levels of testosterone correlated with greater frontal alpha asymmetry in women. Source localization found that frontal asymmetry was driven by decreased alpha power in right inferior frontal gyrus that correlated with increased behavioral inhibition in women. Together, these findings might explain inconsistencies in previous investigation on frontal alpha asymmetry., (Copyright © 2021 Elsevier B.V. All rights reserved.)

New Findings: What is the central question of this study? Glucose is the dominant energy source for the brain. However, little is known about how glucose metabolism impacts the coordination of network activity in the brain in healthy adults. What is the main finding and its importance? We demonstrate that both α oscillations and the aperiodic signal components of the resting EEG are modulated by experimentally elevated blood glucose concentrations. Our findings suggest that glucose increases measures associated with excitation-inhibition (E:I) balance, but that the effect on α oscillations might plateau. Understanding the relationship between glucose consumption and E:I balance is crucial to developing our understanding of how metabolism shapes human brain activity., Abstract: Brain network oscillations can be divided broadly into periodic and aperiodic signal components, which are sensitive to state-dependent changes in network coordination and excitation-inhibition (E:I) balance. We sought to address whether the dominant energy source of the brain, glucose, is implicated in the regulation of network activity and excitability. We conducted an experimenter-blind, crossover study of the effect of blood glucose level (BGL) on the resting EEG frequency spectrum. Participants consumed a glucose drink (75 g glucose) or an equivalent volume of water on two separate visits. EEG data were sampled before and ≤3 h after the drink. We found that the experimentally induced changes in BGL exhibited an inverted U-shaped relationship, with changes in the individual α frequency peak, whereas the slope of the aperiodic signal component of the frequency spectrum showed a positive linear association suggestive of greater excitation. In contrast, peak α power, which is typically associated with top-down inhibitory processes, was negatively associated with changes in BGL. Collectively, these results suggest that high BGL alters brain network coordination in the form of α oscillations and measures associated with E:I balance., (© 2021 The Authors. Experimental Physiology © 2021 The Physiological Society.)

With the emergence of glycated hemoglobin as a diagnostic test for diabetes, oral glucose tolerance tests (OGTTs) have become rare in endocrinology practice. As they have moved out of favor, the importance of patient instructions on preparation prior to OGTT has faded from memory. Decades-old literature, well-known to endocrinologists a generation ago, emphasized the importance of carbohydrate intake prior to OGTT. In this expert endocrine consult, we discuss an OGTT performed in a research setting without adequate carbohydrate intake at the evening meal prior to the OGTT. The resultant elevated plasma glucose levels at 1-hour and 2-hours mimicked the loss of first-phase insulin release seen in early type 1 and type 2 diabetes. With clinical concern that the research participant had evolving type 1 or type 2 diabetes, the volunteer was subjected to additional testing and experienced anxiety. Repeat OGTT was normal after adequate carbohydrate intake (>150 grams/day and >50 grams the evening prior to overnight fast for the study). The physiology of this phenomenon is explored and is likely mediated through beta cell adaptation and alteration in peripheral glucose uptake in response to nutrient exposure. The learnings of decades ago have clearly faded, and this literature should be revisited to ensure that OGTT results are not compromised when ordered for clinical or research purposes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)