Ferret as a model system for studying the anatomy and function of the prefrontal cortex: A systematic review.

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.

Internal Representations Are Prioritized by Frontoparietal Theta Connectivity and Suppressed by alpha Oscillation Dynamics: Evidence from Concurrent Transcranial Magnetic Stimulation EEG and Invasive EEG.

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.

Causal oscillations in the visual thalamo-cortical network in sustained attention in ferrets.

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.

Crowd-sourced investigation of a potential relationship between Bartonella-associated cutaneous lesions and neuropsychiatric symptoms.

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.

Contrast detection is enhanced by deterministic, high-frequency transcranial alternating current stimulation with triangle and sine waveform.

Stochastic resonance (SR) describes a phenomenon where an additive noise (stochastic carrier-wave) enhances the signal transmission in a nonlinear system. In the nervous system, nonlinear properties are present from the level of single ion channels all the way to perception and appear to support the emergence of SR. For example, SR has been repeatedly demonstrated for visual detection tasks, also by adding noise directly to cortical areas via transcranial random noise stimulation (tRNS). When dealing with nonlinear physical systems, it has been suggested that resonance can be induced not only by adding stochastic signals (i.e., noise) but also by adding a large class of signals that are not stochastic in nature that cause "deterministic amplitude resonance" (DAR). Here, we mathematically show that high-frequency, deterministic, periodic signals can yield resonance-like effects with linear transfer and infinite signal-to-noise ratio at the output. We tested this prediction empirically and investigated whether nonrandom, high-frequency, transcranial alternating current stimulation (tACS) applied to the visual cortex could induce resonance-like effects and enhance the performance of a visual detection task. We demonstrated in 28 participants that applying 80-Hz triangular-waves or sine-waves with tACS reduced the visual contrast detection threshold for optimal brain stimulation intensities. The influence of tACS on contrast sensitivity was equally effective to tRNS-induced modulation, demonstrating that both tACS and tRNS can reduce contrast detection thresholds. Our findings suggest that a resonance-like mechanism can also emerge when deterministic electrical waveforms are applied via tACS.NEW & NOTEWORTHY Our findings extend our understanding of neuromodulation induced by noninvasive electrical stimulation. We provide the first evidence showing acute online benefits of transcranial alternating current stimulation (tACS)triangle and tACSsine targeting the primary visual cortex (V1) on visual contrast detection in accordance with the resonance-like phenomenon. The "deterministic" tACS and "stochastic" high-frequency-transcranial random noise stimulation (tRNS) are equally effective in enhancing visual contrast detection.

Dissection of neuronal circuits underlying sustained attention with the five-choice serial reaction time task.

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.

Day-to-day individual alpha frequency variability measured by a mobile EEG device relates to anxiety.

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.

Mental Activity as the Bridge between Neural Biomarkers and Symptoms of Psychiatric Illness.

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.

Alpha transcranial alternating current stimulation reduces depressive symptoms in people with schizophrenia and auditory hallucinations: a double-blind, randomized pilot clinical trial.

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.

Digitalized transcranial electrical stimulation: A consensus statement.

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.

Autonomic and Depression Symptoms in Parkinson's Disease: Clinical Evidence for Overlapping Physiology.

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.

Cell type-specific excitability probed by optogenetic stimulation depends on the phase of the alpha oscillation.

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.

Reduction in Left Frontal Alpha Oscillations by Transcranial Alternating Current Stimulation in Major Depressive Disorder Is Context Dependent in a Randomized Clinical Trial.

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.

Reward-Based Decision-Making Engages Distinct Modes of Cross-Frequency Coupling.

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.

Causal role of frontal-midline theta in cognitive effort: a pilot study.

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.