Differences In Neural Mechanisms Research Articles

Social exclusion: differences in neural mechanisms underlying direct versus vicarious experience.

Social exclusion stands as a source of social discord and holds substantial research value. Prior investigations on social exclusion have overlooked the interactive relationship between the excluded individuals and the observers. Hence, this study comparatively explores the neural mechanisms underlying the psychological responses of two distinct roles within the same social exclusion context. A total of 35 pairs (19 pairs of females) participated in the experiment. Within each pair, one individual assumed the role of a socially excluded participant (target), while the other acted as a social exclusion observer. Targets engaged in an online ball-passing game where controlled ball allocations to the participants created an exclusion scenario. Meanwhile, observers spectated the targets playing the game. Throughout the ball-passing activity, functional near-infrared spectroscopy (fNIRS) recorded the blood oxygen data in the prefrontal cortex (PFC) and temporoparietal junction (TPJ) of both participants. Our findings revealed varied levels of rejection sensitivity elicited by direct or observed social exclusion experiences. Additionally, distinct patterns of neural activation were observed: targets displayed conditional differences in the medial prefrontal cortex (mPFC), while male observers exhibited conditional activation differences in the mPFC, and female observers showed conditional activation differences in the right dorsolateral prefrontal cortex (dlPFC). This study juxtaposes the behavioral and neural activation variances between targets and observers within the same social context, offering a novel perspective on investigating the neural mechanisms of social exclusion.

Sex differences in neural responses to emotional facial expressions are associated with lifetime depression and mania risk

IntroductionNo studies systematically examined sex differences in neural mechanisms underlying depression and mania/hypomania risk. Method80 females and 35 males, n = 115(age21.6±1.90) were scanned using 3TfMRI during an implicit emotional-faces task. We examined neural activation to all emotional faces versus baseline, using an anatomical region-of-interest mask comprising regions supporting emotion and salience processing. Sex was a covariate. Extracted parameter estimates(FWE < 0.05,k > 15), age, IQ and their sex interactions were independent variables(IV) in two penalized regression models: dependent variable either MOODS-SR-lifetime, depressive or manic domain score as measures of mania and depression risk. Subsequent Poisson regression models included the non-zero variables identified in the penalized regression models. We tested each model in 2 independent samples. Test sample-I,n = 108(21.6 ± 2.09 years,males/females = 33/75); Test sample-II,n = 93(23.7 ± 2.9 years,males/females = 31/62). ResultsPoisson regression models yielded significant relationships with depression and mania risk: Positive correlations were found between right fusiform activity and depression(beta = 0.610) and mania(beta = 0.690) risk. There was a significant interaction between sex and right fusiform activity(beta = −0.609) related to depression risk, where females had a positive relationship than; and a significant interaction(beta = 0.743) between sex and left precuneus activity related to mania risk, with a more negative relationship in females than males. All findings were replicated in the test samples(qs < 0.05,FDR). LimitationsNo longitudinal follow-up. ConclusionGreater visual attention to emotional faces might underlie greater depression and mania risk, and confer greater vulnerability to depression in females, because of heightened visual attention to emotional faces. Females have a more negative relationship between mania risk and left precuneus activity, suggesting heightened empathy might be associated with reduced mania/hypomania risk in females more than males.

Neural mechanisms of top-down divided and selective spatial attention in visual and auditory perception

Top-down attention mechanisms require the selection of specific objects or locations; however, the brain mechanism involved when attention is allocated across different modalities is not well understood. The aim of this study was to use functional magnetic resonance imaging to define the neural mechanisms underlying divided and selective spatial attention. A concurrent audiovisual stimulus was used, and subjects were prompted to focus on a visual, auditory and audiovisual stimulus in a Posner paradigm. Our behavioral results confirmed the better performance of selective attention compared to devided attention. We found differences in the activation level of the frontoparietal network, visual/auditory cortex, the putamen and the salience network under different attention conditions. We further used Granger causality (GC) to explore effective connectivity differences between tasks. Differences in GC connectivity between visual and auditory selective tasks reflected the visual dominance effect under spatial attention. In addition, our results supported the role of the putamen in redistributing attention and the functional separation of the salience network. In summary, we explored the audiovisual top-down allocation of attention and observed the differences in neural mechanisms under endogenous attention modes, which revealed the differences in cross-modal expression in visual and auditory attention under attentional modulation.

Major gender differences in relations between life stressor frequency and gray matter in adolescence and emerging adulthood.

Adolescence and emerging adulthood is likely a sensitive period for the neural effects of stress due to increasing life stress, onset of stress-related disorders, and continued gray matter (GM) development. In adults, stress is associated with GM differences in the medial prefrontal cortex (mPFC), hippocampus, and amygdala, but little is known about these relations, and whether they differ by gender, during adolescence and emerging adulthood. Further, it is unknown whether dependent (self-generated) and independent (fateful) stressors have distinct associations with GM, as each have distinct relations with internalizing psychopathology. We tested relations between recent dependent and independent stressor frequency (ALEQ-R) and GM structure using MRI in a priori regions of interest (mPFC, amygdala, and hippocampus) and across the cortex in youth from the Denver/Boulder metro area ages 14-22 (N = 144). Across both genders, no effects passed multiple comparison correction (FDR q > .05). However, there were significant differences between male and female youth (FDR q < .05), with opposite relations between dependent stressor frequency and cortical GM thickness in the salience network and emotion regulation regions and with surface area in default mode network regions. These results motivate future investigations of gender differences in neural mechanisms of stress generation and reactivity. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Neural Correlates of Audiovisual Speech Processing in Autistic and Non-Autistic Youth.

Autistic youth demonstrate differences in processing multisensory information, particularly in temporal processing of multisensory speech. Extensive research has identified several key brain regions for multisensory speech processing in non-autistic adults, including the superior temporal sulcus (STS) and insula, but it is unclear to what extent these regions are involved in temporal processing of multisensory speech in autistic youth. As a first step in exploring the neural substrates of multisensory temporal processing in this clinical population, we employed functional magnetic resonance imaging (fMRI) with a simultaneity-judgment audiovisual speech task. Eighteen autistic youth and a comparison group of 20 non-autistic youth matched on chronological age, biological sex, and gender participated. Results extend prior findings from studies of non-autistic adults, with non-autistic youth demonstrating responses in several similar regions as previously implicated in adult temporal processing of multisensory speech. Autistic youth demonstrated responses in fewer of the multisensory regions identified in adult studies; responses were limited to visual and motor cortices. Group responses in the middle temporal gyrus significantly interacted with age; younger autistic individuals showed reduced MTG responses whereas older individuals showed comparable MTG responses relative to non-autistic controls. Across groups, responses in the precuneus covaried with task accuracy, and anterior temporal and insula responses covaried with nonverbal IQ. These preliminary findings suggest possible differences in neural mechanisms of audiovisual processing in autistic youth while highlighting the need to consider participant characteristics in future, larger-scale studies exploring the neural basis of multisensory function in autism.

Typical and atypical neural mechanisms support spoken word processing in Angelman syndrome

Angelman syndrome (AS) is known to affect expressive and receptive communication abilities. This study examined individual differences in neural mechanisms underlying speech processing in children with AS (n = 24, M age = 10.01 years) and typical development (n = 30, M age = 10.82 years) using auditory event-related potentials during passive listening to common English words and novel pseudowords. A group of adults with AS (n = 7, M = 31.78 years) provided data about the upper developmental range. The typically developing group demonstrated the expected more negative amplitudes in response to words than pseudowords within 250–500 ms after stimulus onset at the left temporal scalp region. Children and adults with AS exhibited a similar left-lateralized pattern of word-pseudoword differentiation at temporal and parietal regions, but not the midline parietal memory response for known words observed in the typically developing group, suggesting typical-like word-pseudoword differentiation along with possible alterations in the automatic recall of word meaning. These results have important implications for understanding receptive and expressive communication processes in AS and support the use of auditory neural responses for characterizing individual differences in neurodevelopmental disorders with limited speech.

Brain Network Research of Skilled Shooters in the Shooting Preparation Stage under the Condition of Limited Sensory Function.

Shooting is a sport dominated by psychological factors. Hence, disturbing the shooter’s sensory function during aiming will seriously affect his psychological state and shooting performance. Electroencephalograph (EEG) measurements of 30 skilled marksmen in the shooting preparation stage under noisy disturbance, weak light, and normal conditions were recorded. Therefore, the differences in neural mechanisms in the shooter’s brain during shooting aiming in different disturbance conditions were explored using an analytical approach that employs functional connectivity and brain network analysis based on graph theory. The relationship between these brain network characteristics and shooting performance was also compared. The results showed that (1) the average connection strength in the beta frequency band and connection intensity in the left and right temporal lobes of the shooters under noise disturbance were significantly higher than those under the other two conditions, and their brain networks also showed a higher global and local efficiency. In addition, (2) the functional connection intensity in the occipital region of the beta band was higher than that in the normal condition in the weak-light condition. The information interaction in the left parietal region also increased continually during the shooting process. (3) Furthermore, the shooters’ eigenvector centrality in the temporal and occipital regions with limited sensory function in the two conditions was lower than those in the normal condition. These findings suggest that noise disturbance activates the arousal level of the shooter’s brain and enhances the information processing efficiency of the brain network; however, it increases the mental workload. In weak-light conditions, shooters focus more on visual information processing during aiming and strengthen the inhibition of functions in the brain regions unrelated to shooting behavior. Audiovisual disturbance renders the cortical regions equivalent to the audiovisual perception function in the shooter’s brain less important in the entire brain network than in the normal condition. Therefore, these findings reveal the effect of audiovisual disturbance on the functional network of the cortex in the shooting preparation stage and provide a theoretical basis for further understanding the neural mechanism of the shooting process under sensory disturbances.

Sex differences in neural mechanisms of social and non-social threat monitoring

Adolescent males and females differ in their responses to social threat. Yet, threat processing is often probed in non-social contexts using the error-related negativity (ERN; Flanker EEG Task), which does not yield sex-specific outcomes. fMRI studies show inconsistent patterns of sex-specific neural engagement during threat processing. Thus, the relation between threat processing in non-social and social contexts across sexes and the effects perceived level of threat on brain function are unclear. We tested the interactive effect of non-social threat-vigilance (ERN), sex (N = 69; Male=34; 11–14-year-olds), and perceived social threat on brain function while anticipating feedback from ‘unpredictable’, ‘nice’, or ‘mean’ purported peers (fMRI; Virtual School Paradigm). Whole-brain analyses revealed differential engagement of precentral and inferior frontal gyri, putamen, anterior cingulate cortex, and insula. Among males with more threat-vigilant ERNs, greater social threat was associated with increased activation when anticipating unpredictable feedback. Region of interest analyses revealed this same relation in females in the amygdala and anterior hippocampus when anticipating mean feedback. Thus, non-social threat vigilance relates to neural engagement depending on perceived social threat, but peer-based social contexts and brain regions engaged, differ across sexes. This may partially explain divergent psychosocial outcomes in adolescence.

Contrasting attentional biases in a saccadic choice task.

To gain insight into how human observers select items in the visual field we pitted two attentional biases against one another in a single free choice design. The first bias is the nasal-temporal asymmetry during free choice tasks, where observers tend to choose targets that appear in their temporal hemifield over targets appearing in their nasal hemifield. The second is the choice bias found in studies of attentional priming. When observers have to select between a stimulus that shares features with a preceding target and a stimulus sharing features with previous distractors, they have a strong tendency to choose the preceding search target and this bias increases the more often the same search is repeated. Our results show that both biases affect saccadic choice, but they also show that the nasal-temporal bias can modulate the strength of the priming effects, but not vice versa. The priming effect was stronger for stimuli appearing in the temporal than in the nasal hemifield, but the nasal-temporal bias was similar for primed and unprimed targets. Additionally, our findings are the first to show how search repetition leads to faster saccades. The observed difference between the effects of the NTA and priming biases may reflect the difference in neural mechanisms thought to be behind these biases and that biases at lower levels may outrank higher-level biases, at least in their effect on visual attention.

Effects of Aging on the Neural Mechanisms Underlying the Recollection of Memories Encoded by Social Interactions With Persons in the Same and Different Age Groups.

Memories related to ingroup members are remembered more accurately than those related to outgroup members. However, little is known about the age-dependent differences in neural mechanisms underlying the retrieval of memories shared with ingroup or outgroup members that are categorized by age-group membership. The present functional magnetic resonance imaging (fMRI) study investigated this issue. Healthy young and older adults participated in a 2-day experiment. On the first day outside fMRI, participants were presented with words by unfamiliar persons in movie clips and exchanged each word with persons belonging to the same age group (SAG) or different age group (DAG). On the second day during fMRI, participants were randomly presented with learned and new words one by one, and they judged whether each word had been encoded with either SAG or DAG members or neither. fMRI results demonstrated that an age-dependent decrease in successful retrieval activation of memories presented by DAG was identified in the anterior temporal lobe (ATL) and hippocampus, whereas with memories presented by SAG, an age-dependent decrease in activation was not found in any regions. In addition, an age-dependent decrease in functional connectivity was significant between the hippocampus/ATL and posterior superior temporal sulcus (pSTS) during the successful retrieval of memories encoded with the DAG people. The “other”-related mechanisms including the hippocampus, ATL, and pSTS with memories learned with the outgroup members could decrease in older adults, whereas with memories learned with the ingroup members, the “self”-related mechanisms could be relatively preserved in older adults.

Neuroimaging of the Syllable Repetition Task in Children With Residual Speech Sound Disorder.

Purpose This study investigated phonological and speech motor neural networks in children with residual speech sound disorder (RSSD) during an overt Syllable Repetition Task (SRT). Method Sixteen children with RSSD with /ɹ/ errors (6F [female]; ages 8;0-12;6 [years;months]) and 16 children with typically developing speech (TD; 8F; ages 8;5-13;7) completed a functional magnetic resonance imaging experiment. Children performed the SRT ("SRT-Early Sounds") with the phonemes /b, d, m, n, ɑ/ and an adapted version ("SRT-Late Sounds") with the phonemes /ɹ, s, l, tʃ, ɑ/. We compared the functional activation and transcribed production accuracy of the RSSD and TD groups during both conditions. Expected errors were not scored as inaccurate. Results No between-group or within-group differences in repetition accuracy were found on the SRT-Early Sounds or SRT-Late Sounds tasks at any syllable sequence length. On a first-level analysis of the tasks, the TD group showed expected patterns of activation for both the SRT-Early Sounds and SRT-Late Sounds, including activation in the left primary motor cortex, left premotor cortex, bilateral anterior cingulate, bilateral primary auditory cortex, bilateral superior temporal gyrus, and bilateral insula. The RSSD group showed similar activation when correcting for multiple comparisons. In further exploratory analyses, we observed the following subthreshold patterns: (a) On the SRT-Early Sounds, greater activation was found in the left premotor cortex for the RSSD group, while greater activation was found in the left cerebellum for the TD group; (b) on the SRT-Late Sounds, a small area of greater activation was found in the right cerebellum for the RSSD group. No within-group functional differences were observed (SRT-Early Sounds vs. SRT-Late Sounds) for either group. Conclusions Performance was similar between groups, and likewise, we found that functional activation did not differ. Observed functional differences in previous studies may reflect differences in task performance, rather than fundamental differences in neural mechanisms for syllable repetition.

Sex differences in executive control: A systematic review of functional neuroimaging studies.

The number of studies investigating sex differences in executive functions, particularly those using human functional neuroimaging techniques, has risen dramatically in the past decade. However, the influences of sex on executive function are still underexplored and poorly characterized. To address this, we conducted a systematic literature review of functional neuroimaging studies investigating sex differences in three prominent executive control domains of cognitive set-shifting, performance monitoring, and response inhibition. PubMed, Web of Science, and Scopus were systematically searched. Following the application of exclusion criteria, 21 studies were included, with a total of 677 females and 686 males. Ten of these studies were fMRI and PET, eight were EEG, and three were NIRS. At present, there is evidence for sex differences in the neural networks underlying all tasks of executive control included in this review suggesting males and females engage different strategies depending on task demands. There was one task exception, the 2-Back task, which showed no sex differences. Due to methodological variability and the involvement of multiple neural networks, a simple overarching statement with regard to gender differences during executive control cannot be provided. As such, we discuss limitations within the current literature and methodological considerations that should be employed in future research. Importantly, sex differences in neural mechanisms are present in the majority of tasks assessed, and thus should not be ignored in future research. PROSPERO registration information: CRD42019124772.

Dynamic Causal Modeling of Gender Differences in Emotion: Implications for Augmented Cognition

The goal of this study is to investigate the neural basis of gender difference in emotion processing. Elec- troencephalogram (EEG) signals were recorded when the same set of emotion-eliciting images was shown to male and female participants. Neural connections were estimated using Dynamic Causal Modeling (DCM) and results for both genders were compared. We found that dorsolateral prefrontal cortex exerts modulatory effects differently for males and females. These findings on the gender differences in neural mechanisms of emotion processing may be utilized in applications of the augmented cognition program.

Differential Changes in Early Somatosensory Evoked Potentials between the Dominant and Non-Dominant Hand, Following a Novel Motor Tracing Task.

During training in a novel dynamic environment, the non-dominant upper limb favors feedback control, whereas the dominant limb favors feedforward mechanisms. Early somatosensory evoked potentials (SEPs) offer a means to explore differences in cortical regions involved in sensorimotor integration (SMI). This study sought to compare differences in SMI between the right (Dom) and left (Non-Dom) hand in healthy right-handed participants. SEPs were recorded in response to median nerve stimulation, at baseline and post, a motor skill acquisition-tracing task. One group (n = 12) trained with their Dom hand and the other group (n = 12), with their Non-Dom hand. The Non-Dom hand was significantly more accurate at baseline (p < 0.0001) and both groups improved with time (p < 0.0001), for task accuracy, with no significant interaction effect between groups for both post-acquisition and retention. There were significant group interactions for the N24 (p < 0.001) and the N30 (p < 0.0001) SEP peaks. Post motor acquisition, the Dom hand had a 28.9% decrease in the N24 and a 23.8% increase in the N30, with opposite directional changes for the Non-Dom hand; 22.04% increase in N24 and 24% decrease in the N30. These SEP changes reveal differences in early SMI between Dom and Non-Dom hands in response to motor acquisition, providing objective, temporally sensitive measures of differences in neural mechanisms between the limbs.

The Neural Mechanism of the Social Framing Effect: Evidence from fMRI and tDCS Studies.

As an important cognitive bias, the framing effect shows that our decision preferences are sensitive to the verbal description (i.e., frame) of options. This study focuses on the neural underpinnings of the social framing effect, which is based on decision-making regarding other people. A novel paradigm was used in which participants made a trade-off between economic benefits and the feelings of others. This decision was described as either a "harm" to, or "not helping," other persons in two conditions (Harm frame vs Help frame). Both human males and females were recruited. Participants behaved more prosocially for Harm frame compared with Help frame, resulting in a significant social framing effect. Using functional magnetic resonance imaging, Experiment 1 showed that the social framing effect was associated with stronger activation in the temporoparietal junction (TPJ), especially its right part. The functional connectivity between the right TPJ (rTPJ) and medial prefrontal cortex predicted the social framing effect on the group level. In Experiment 2, we used transcranial direct current stimulation to modulate the activity of the rTPJ and found that the social framing effect became more prominent under anodal (excitatory) stimulation, while the nonsocial framing effect elicited by the economic gain/loss gambling frame remained unaffected. The rTPJ results might be associated with moral conflicts modulated by the social consequences of an action or different levels of mentalizing with others under different frame conditions, but alternative interpretations are also worth noting. These findings could help elucidate the psychological mechanisms of the social framing effect.SIGNIFICANCE STATEMENT Previous studies have suggested that the framing effect is generated from an interaction between the amygdala and anterior cingulate cortex. This opinion, however, is based on findings from nonsocial framing tasks. Recent research has highlighted the importance of distinguishing between the social and nonsocial framing effects. The current study focuses on the social framing effect and finds out that the temporoparietal junction and its functional connectivity with the medial prefrontal cortex play a significant role. Additionally, modulating the activity of this region leads to changes in social (but not nonsocial) framing effect. Broadly speaking, these findings help understand the difference in neural mechanisms between social and nonsocial decision-making. Meanwhile, they might be illuminating to promote helping behavior in society.

Differences in network centrality between high and low myopia: a voxel-level degree centrality study.

Previous studies have linked high myopia (HM) to brain activity, and the difference between HM and low myopia (LM) can be assessed. To study the differences in functional networks of brain activity between HM and LM by the voxel-level degree centrality (DC) method. Twenty-eight patients with HM (10 men, 18 women), 18 patients with LM (4 men, 14 women), and 59 healthy controls (27 men, 32 women) were enrolled in this study. The voxel-level DC method was used to assess spontaneous brain activity. Correlation analysis was used to explore the change of average DC value in different brain regions, in order to analyze differences in brain activity between HM and LM. DC values of the right cerebellum anterior lobe/brainstem, right parahippocampal gyrus, and left caudate in HM patients were significantly higher than those in LM patients (P < 0.05). In contrast, DC values of the left medial frontal gyrus, right inferior frontal gyrus, left middle frontal gyrus, and left inferior parietal lobule were significantly lower in patients with HM (P < 0.05). However, there was no correlation between behavior and average DC values in different brain regions (P < 0.05). Different changes in brain regions between HM and LM may indicate differences in neural mechanisms between HM and LM. DC values could be useful as biomarkers for differences in brain activity between patients with HM and LM. This study provides a new method to assess differences in functional networks of brain activity between patients with HM and LM.

Corticostriatal Hyperactivation to Reward Presentation in Individuals With TBI With High Depressive Symptomatology: A Pilot Study.

To examine the impact of depression on neural mechanisms associated with outcome processing (rewarding and punishing outcomes) in persons with traumatic brain injury (TBI). Kessler Foundation's Rocco Ortenzio Neuroimaging Center. A total of 16 adults with moderate to severe TBI. Chicago Multiscale Depression Inventory (CMDI); Behavioral Inhibition/Behavioral Activation Scale (BIS/BAS); functional MRI of the head while performing a gambling task, with a reward (+$1.00) and punishment (-$0.50). Individuals with TBI reporting high depressive symptomatology exhibited increased activation in the ventromedial prefrontal cortex (VMPFC) and striatum during presentation of rewarding outcomes compared with individuals with TBI reporting low depressive symptomatology. Punishing outcome presentation was not associated with any change in brain activation. No differences in volume of the striatum and VMPFC were observed between groups. Current findings provide the first evidence of differences in neural mechanisms underlying outcome processing between individuals with TBI with and without depression. The results suggest that depressive symptomatology might have a different effect on individuals with TBI than what is typically observed in individuals without TBI reporting with depression, with the possibility of rewards becoming more reinforcing as depressive symptomatology increases. Future studies should explore the potential implications of behavioral responses to rewards and punishments in TBI and how they can affect rehabilitation approaches and activities of daily living.

Global Motion Perception in Autism Spectrum Disorder: A Meta-Analysis

Visual perception in individuals with autism spectrum disorder (ASD) is often debated in terms of enhanced local and impaired global perception. Deficits in global motion perception seem to support this characterization, although the evidence is inconsistent. We conducted a large meta-analysis on global motion, combining 48 articles on biological and coherent motion. Results provide evidence for a small global motion processing deficit in individuals with ASD compared to controls in both biological and coherent motion. This deficit appears to be present independent of the paradigm, task, dependent variable, age or IQ of the groups. Results indicate that individuals with ASD are less sensitive to these types of global motion, although the difference in neural mechanisms underlying this behavioral difference remains unclear.

Active touch facilitates object size perception in children but not adults: A multisensory event related potential study

In order to increase perceptual precision the adult brain dynamically combines redundant information from different senses depending on their reliability. During object size estimation, for example, visual, auditory and haptic information can be integrated to increase the precision of the final size estimate. Young children, however, do not integrate sensory information optimally and instead rely on active touch. Whether this early haptic dominance is reflected in age-related differences in neural mechanisms and whether it is driven by changes in bottom-up perceptual or top-down attentional processes has not yet been investigated. Here, we recorded event-related-potentials from a group of adults and children aged 5–7 years during an object size perception task using auditory, visual and haptic information. Multisensory information was presented either congruently (conveying the same information) or incongruently (conflicting information). No behavioral responses were required from participants. When haptic size information was available via actively tapping the objects, response amplitudes in the mid-parietal area were significantly reduced by information congruency in children but not in adults between 190 ms–250 ms and 310 ms–370 ms. These findings indicate that during object size perception only children’s brain activity is modulated by active touch supporting a neural maturational shift from sensory dominance in early childhood to optimal multisensory benefit in adulthood.

Sex differences in neural mechanisms mediating reward and addiction.

There is increasing evidence in humans and laboratory animals for biologically based sex differences in every phase of drug addiction: acute reinforcing effects, transition from occasional to compulsive use, withdrawal-associated negative affective states, craving, and relapse. There is also evidence that many qualitative aspects of the addiction phases do not differ significantly between males and females, but one sex may be more likely to exhibit a trait than the other, resulting in population differences. The conceptual framework of this review is to focus on hormonal, chromosomal, and epigenetic organizational and contingent, sex-dependent mechanisms of four neural systems that are known-primarily in males-to be key players in addiction: dopamine, mu-opioid receptors (MOR), kappa opioid receptors (KOR), and brain-derived neurotrophic factor (BDNF). We highlight data demonstrating sex differences in development, expression, and function of these neural systems as they relate-directly or indirectly-to processes of reward and addictive behavior, with a focus on psychostimulants and opioids. We identify gaps in knowledge about how these neural systems interact with sex to influence addictive behavior, emphasizing throughout that the impact of sex can be highly nuanced and male/female data should be reported regardless of the outcome.