Functional Magnetic Resonance Imaging Studies in Sexual Medicine: A Primer.

BACKGROUND: Over the past 30 years, functional magnetic resonance imaging (fMRI) has emerged as a powerful tool to non-invasively study the activity and function of the human brain. But along with the potential of fMRI to shed light on neurological, psychiatric, and psychological processes, there are methodological challenges and criticisms. AIM: We herein provide an fMRI primer designed for a diverse audience, from the neuroimaging novice to the experienced user. METHODS: This primer is structured as follows: Part 1: Overview: "What is fMRI and what can it tell us?." Part 2: Basic fMRI principles: MR physics, the BOLD signal, and components of a typical scan session. Part 3: Basic fMRI experimental design: why timing is critical, and common sources of noise in the signal. Part 4: Basic fMRI analysis methods: software, the 3 stages of data analysis (preprocessing, individual, and group level), and a survey of advanced topics and methods including connectivity, machine learning, and assessing statistical significance. Part 5: Criticism, crises, and opportunities related to power of studies, computing requirements, logistical, and interpretational challenges, and methodological debate (assessing causality, circular correlations, and open science best practices). OUTCOMES N/A CLINICAL TRANSLATION: fMRI has primarily been used in clinical research to elucidate the brain correlates of sexual behavior. The translational potential of the method into clinical practice has not yet been realizedfMRI has primarily been used in clinical research to elucidate the brain correlates of sexual behavior. The translational potential of the method into clinical practice has not yet been realized STRENGTHS AND LIMITATIONS: fMRI is a useful and powerful tool for understanding the brain basis of human sexuality. However, it is also expensive, requires extensive methods expertise, and lacks the precision needed to be immediately translatable to clinical practice. The recency of the method, need for basic research, technical limitations, as well as inherent variability in individuals brain activity also impact the pace at which fMRI for sexual medicine can move from the scanner to the clinic. CONCLUSION: This primer provides the novice an understanding of the appropriate uses and limitations of fMRI, and for the experienced user, a concise update on current issues and methodological advances. Mills-Finnerty C, Frangos E, Allen K, et al. Functional Magnetic Resonance Imaging Studies in Sexual Medicine: A Primer. J Sex Med 2022;19:1073-1089.

Experimental evidence for a child-to-adolescent switch in human amygdala-prefrontal cortex communication: A cross-sectional pilot study.

Interactions between the amygdala and prefrontal cortex are fundamental to human emotion. Despite the central role of frontoamygdala communication in adult emotional learning and regulation, little is known about how top-down control emerges during human development. In the present cross-sectional pilot study, we experimentally manipulated prefrontal engagement to test its effects on the amygdala during development. Inducing dorsal anterior cingulate cortex (dACC) activation resulted in developmentally-opposite effects on amygdala reactivity during childhood versus adolescence, such that dACC activation was followed by increased amygdala reactivity in childhood but reduced amygdala reactivity in adolescence. Bayesian network analyses revealed an age-related switch between childhood and adolescence in the nature of amygdala connectivity with the dACC and ventromedial PFC (vmPFC). Whereas adolescence was marked by information flow from dACC and vmPFC to amygdala (consistent with that observed in adults), the reverse information flow, from the amygdala to dACC and vmPFC, was dominant in childhood. The age-related switch in information flow suggests a potential shift from bottom-up co-excitatory to top-down regulatory frontoamygdala connectivity and may indicate a profound change in the circuitry supporting maturation of emotional behavior. These findings provide novel insight into the developmental construction of amygdala-cortical connections and implications for the ways in which childhood experiences may influence subsequent prefrontal function.

Brain network response underlying decisions about abstract reinforcers.

Decision making studies typically use tasks that involve concrete action-outcome contingencies, in which subjects do something and get something. No studies have addressed decision making involving abstract reinforcers, where there are no action-outcome contingencies and choices are entirely hypothetical. The present study examines these kinds of choices, as well as whether the same biases that exist for concrete reinforcer decisions, specifically framing effects, also apply during abstract reinforcer decisions. We use both General Linear Model as well as Bayes network connectivity analysis using the Independent Multi-sample Greedy Equivalence Search (IMaGES) algorithm to examine network response underlying choices for abstract reinforcers under positive and negative framing. We find for the first time that abstract reinforcer decisions activate the same network of brain regions as concrete reinforcer decisions, including the striatum, insula, anterior cingulate, and VMPFC, results that are further supported via comparison to a meta-analysis of decision making studies. Positive and negative framing activated different parts of this network, with stronger activation in VMPFC during negative framing and in DLPFC during positive, suggesting different decision making pathways depending on frame. These results were further clarified using connectivity analysis, which revealed stronger connections between anterior cingulate, insula, and accumbens during negative framing compared to positive. Taken together, these results suggest that not only do abstract reinforcer decisions rely on the same brain substrates as concrete reinforcers, but that the response underlying framing effects on abstract reinforcers also resemble those for concrete reinforcers, specifically increased limbic system connectivity during negative frames.

Affective neuroscience: applications for sexual medicine research and clinical practice.

INTRODUCTION: Affective neuroscience is the study of the brain substrates of emotional, embodied experiences. Affective neuroscience theory (ANT) is based on experimental evidence that all mammals are hardwired with 7 primary subcortical emotional operating systems, or "core emotions," that have overlapping but distinct circuits buried in the deep, ancient parts of the brain. Imbalances in the 7 core emotions can affect multiple aspects of the individual's psychosocial well-being (eg, depression, anxiety, substance abuse). Here, we propose that core emotions can also influence sexual function and, specifically, that imbalances in core emotions are the bridge connecting psychiatric symptoms (eg, anhedonia) to sexual dysfunction (eg, anorgasmia). OBJECTIVES: In this targeted review and commentary, we outline potential connections between ANT and sexual medicine research and clinical practice. We summarize ANT by defining the 3-level BrainMind and core emotions; examining how they relate to personality, behavior, and mental health; and determining the implications for sexual health research and clinical practice. METHODS: A targeted literature review was conducted. Case studies were adapted from client files and clinician interviews and then anonymized. RESULTS: We propose a novel organizational schema for implementing affective balance therapies for sexual dysfunction, which integrate psychoeducational, somatic, and cognitive therapeutic approaches under the ANT framework. We provide 3 patient case studies (anorgasmia, hypersexuality, spinal cord injury) outlining the implementation of this approach and patient outcomes. CONCLUSION: ANT has practical translational applications in sexual health research and clinical practice. By integrating our understanding of the role of core emotions in human sexuality, clinicians can better tailor treatments to address sexual dysfunction.

Protocol optimization and reducing dropout in online research.

Online research has advantages over in-person research; it's cost-efficient, scalable, and may increase diversity. Researchers collecting data online can assess protocol performance with classification models like a decision tree. However, challenges include attrition, lack of testing environment controls, technical limitations, and lack of face-to-face rapport and real time feedback. It is necessary to consider human factors of the teleresearch process from recruitment to data collection. Here we document the impact of protocol optimizations on social media engagement and retention between a pilot sample of Veterans (n = 26) and a post-optimization sample of both Veterans and civilians (n = 220) recruited from Facebook advertisements. Two-sided tests for equality of proportions were statistically significant: advertisement views leading to clicks increased by 23.8% [X2(1) = 130.3, p < 0.001] and completion of behavioral tasks increased by 31.2% [X2(1) = 20.74, p < 0.001]. However, a proportion of participants dropped out of the study before completion for both samples. To explore why, a C5.0 decision tree was used to find features that classify participant dropout. The features chosen by the algorithm were nicotine use (100%) and cannabis use (25.6%). However, for those completing the study, data quality of cognitive performance was similar for users and nonusers. Rather than determining eligibility, participants who endorse using nicotine, or both nicotine and cannabis, may have individual differences that require support in online protocols to reduce drop out, such as extra breaks. An introduction page that humanizes participants' lifestyle habits as a naturalistic benefit of remote research may also be helpful. Strategies are discussed to increase engagement and improve data quality. The findings have implications for the feasibility of conducting remote research, an increasingly popular approach that has distinct challenges compared to in-person studies.

Transcutaneous Vagus Nerve Stimulation (tVNS) applications in cognitive aging: a review and commentary.

Differentiating healthy from pathological aging trajectories is extremely timely, as the global population faces an inversion where older adults will soon outnumber younger 5:1. Many cognitive functions (e.g., memory, executive functions, and processing speed) decline with age, a process that can begin as early as midlife, and which predicts subsequent diagnosis with dementia. Although dementia is a devastating and costly diagnosis, there remains limited evidence for medications, therapies, and devices that improve cognition or attenuate the transition into dementia. There is an urgent need to intervene early in neurodegenerative processes leading to dementia (e.g., depression and mild cognitive impairment). In this targeted review and commentary, we highlight transcutaneous Vagus Nerve Stimulation (tVNS) as a neurostimulation method with unique opportunities for applications in diseases of aging, reviewing recent literature, feasibility of use with remote data collection methods/telehealth, as well as limitations and conflicts in the literature. In particular, small sample sizes, uneven age distributions of participants, lack of standardized protocols, and oversampling of non-representative groups (e.g., older adults with no comorbid diagnoses) limit our understanding of the potential of this method. We offer recommendations for how to improve representativeness, statistical power, and generalizability of tVNS research by integrating remote data collection techniques.

Association between mental health symptoms and behavioral performance in younger vs. older online workers.

Background: The COVID-19 pandemic has been associated with increased rates of mental health problems, particularly in younger people. Objective: We quantified mental health of online workers before and during the COVID-19 pandemic, and cognition during the early stages of the pandemic in 2020. A pre-registered data analysis plan was completed, testing the following three hypotheses: reward-related behaviors will remain intact as age increases; cognitive performance will decline with age; mood symptoms will worsen during the pandemic compared to before. We also conducted exploratory analyses including Bayesian computational modeling of latent cognitive parameters. Methods: Self-report depression (Patient Health Questionnaire 8) and anxiety (General Anxiety Disorder 7) prevalence were compared from two samples of Amazon Mechanical Turk (MTurk) workers ages 18-76: pre-COVID 2018 (N = 799) and peri-COVID 2020 (N = 233). The peri-COVID sample also completed a browser-based neurocognitive test battery. Results: We found support for two out of three pre-registered hypotheses. Notably our hypothesis that mental health symptoms would increase in the peri-COVID sample compared to pre-COVID sample was not supported: both groups reported high mental health burden, especially younger online workers. Higher mental health symptoms were associated with negative impacts on cognitive performance (speed/accuracy tradeoffs) in the peri-COVID sample. We found support for two hypotheses: reaction time slows down with age in two of three attention tasks tested, whereas reward function and accuracy appear to be preserved with age. Conclusion: This study identified high mental health burden, particularly in younger online workers, and associated negative impacts on cognitive function.

Computations and Connectivity Underlying Aversive Counterfactuals.

Background: Mentally simulating counterfactuals (scenarios that have not actually occurred) is a sophisticated human cognitive function underlying creativity, planning, and daydreaming. One example is the "would you rather" game, in which forced choices are made between outlandish negative counterfactuals. Materials and Methods: We measured behavioral and neural correlates while participants made "would you rather" choices framed as approaching or avoiding aversive counterfactual scenarios (e.g., illnesses, car accidents). Results: We found in two independent cohorts that participants were highly susceptible to framing effects when making these decisions, taking significantly longer to respond to approach frames compared with avoidance. Brain imaging showed that choices to approach and avoid resulted in a pattern of activation consistent with a network associated with responding to aversive stimuli, identified via a coordinate-based meta-analysis of 238 studies. Bayesian graph connectivity analysis showed that network connectivity differed by choice frame, with significantly stronger connectivity for approach choices compared with avoidance choices among primarily limbic nodes (putamen, insula, caudate, and amygdala). Computational modeling of behavior revealed that approach frames led to significantly longer nondecision times, increased evidence required to make decisions, and faster evidence accumulation than avoidance frames. Stronger network connectivity between corticostriatal and limbic regions was associated with rate of evidence accumulation and length of nondecision time during approach choices. For avoidance choices, prefrontal connectivity was related to nondecision time. Conclusions: These results suggest that "would you rather" decisions about aversive counterfactuals differentially recruit limbic circuit connectivity based on choice frame. Impact statement We measured brain connectivity and latent cognitive variables underlying aversive counterfactual choices. We found a replicable reaction time effect whereby approach decisions were slower than avoidance decisions. Computational modeling identified that the latent cognitive variable of evidence accumulation was related to strength of connectivity between corticostriatal and limbic nodes during approach decisions. Multidimensional scaling (MDS) and clustering revealed a three-dimensional choice structure that differed between individuals, and between approach and avoidance choices within individuals. Our results suggest that cognitive evaluations of aversive counterfactuals involve flexible representations that can be altered by choice framing. These findings have broad implications for prospective decision making.

Global connectivity and local excitability changes underlie antidepressant effects of repetitive transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) is a commonly- used treatment for major depressive disorder (MDD). However, our understanding of the mechanism by which TMS exerts its antidepressant effect is minimal. Furthermore, we lack brain signals that can be used to predict and track clinical outcome. Such signals would allow for treatment stratification and optimization. Here, we performed a randomized, sham-controlled clinical trial and measured electrophysiological, neuroimaging, and clinical changes before and after rTMS. Patients (N = 36) were randomized to receive either active or sham rTMS to the left dorsolateral prefrontal cortex (dlPFC) for 20 consecutive weekdays. To capture the rTMS-driven changes in connectivity and causal excitability, resting fMRI and TMS/EEG were performed before and after the treatment. Baseline causal connectivity differences between depressed patients and healthy controls were also evaluated with concurrent TMS/fMRI. We found that active, but not sham rTMS elicited (1) an increase in dlPFC global connectivity, (2) induction of negative dlPFC-amygdala connectivity, and (3) local and distributed changes in TMS/EEG potentials. Global connectivity changes predicted clinical outcome, while both global connectivity and TMS/EEG changes tracked clinical outcome. In patients but not healthy participants, we observed a perturbed inhibitory effect of the dlPFC on the amygdala. Taken together, rTMS induced lasting connectivity and excitability changes from the site of stimulation, such that after active treatment, the dlPFC appeared better able to engage in top-down control of the amygdala. These measures of network functioning both predicted and tracked clinical outcome, potentially opening the door to treatment optimization.

Selective Effects of Psychotherapy on Frontopolar Cortical Function in PTSD.

OBJECTIVE: Exposure therapy is an effective treatment for posttraumatic stress disorder (PTSD), but a comprehensive, emotion-focused perspective on how psychotherapy affects brain function is lacking. The authors assessed changes in brain function after prolonged exposure therapy across three emotional reactivity and regulation paradigms. METHOD: Individuals with PTSD underwent functional MRI (fMRI) at rest and while completing three tasks assessing emotional reactivity and regulation. Individuals were then randomly assigned to immediate prolonged exposure treatment (N=36) or a waiting list condition (N=30) and underwent a second scan approximately 4 weeks after the last treatment session or a comparable waiting period, respectively. RESULTS: Treatment-specific changes were observed only during cognitive reappraisal of negative images. Psychotherapy increased lateral frontopolar cortex activity and connectivity with the ventromedial prefrontal cortex/ventral striatum. Greater increases in frontopolar activation were associated with improvement in hyperarousal symptoms and psychological well-being. The frontopolar cortex also displayed a greater variety of temporal resting-state signal pattern changes after treatment. Concurrent transcranial magnetic stimulation and fMRI in healthy participants demonstrated that the lateral frontopolar cortex exerts downstream influence on the ventromedial prefrontal cortex/ventral striatum. CONCLUSIONS: Changes in frontopolar function during deliberate regulation of negative affect is one key mechanism of adaptive psychotherapeutic change in PTSD. Given that frontopolar connectivity with ventromedial regions during emotion regulation is enhanced by psychotherapy and that the frontopolar cortex exerts downstream influence on ventromedial regions in healthy individuals, these findings inform a novel conceptualization of how psychotherapy works, and they identify a promising target for stimulation-based therapeutics.