Prefrontal Brain Regions Research Articles

Investigational and Therapeutic Applications of Transcranial Magnetic Stimulation in Schizophrenia.

This current review summarizes the investigational and therapeutic applications of transcranial magnetic stimulation (TMS) in schizophrenia. Fairly consistent findings of an impaired cortical excitation-inhibition balance, cortical plasticity, and motor resonance have been reported in schizophrenia. Cortical connectivity impairments have also been demonstrated in motor and prefrontal brain regions. In terms of treatment, the best support is for 1-Hz TMS to the left temporoparietal cortex for the short-term treatment of persistent auditory hallucinations. High-frequency TMS to the left prefrontal cortex improves negative and cognitive symptoms, but with inconsistent and small effects. TMS combined with diverse brain mapping techniques and clinical evaluation can unravel critical brain-behavior relationships relevant to schizophrenia. These provide critical support to the conceptualization of schizophrenia as a connectopathy with anomalous cortical plasticity. Adaptive modulation of these aberrant brain networks in a neuroscience-informed manner drives short-term therapeutic gains in difficult-to-treat symptoms of schizophrenia.

Evidence for a sex-specific contribution of polygenic load for anorexia nervosa to body weight and prefrontal brain structure in nonclinical individuals.

Genetic predisposition and brain structural abnormalities have been shown to be involved in the biological underpinnings of anorexia nervosa (AN). Prefrontal brain regions are suggested to contribute through behavioral inhibition mechanisms to body weight. However, it is unknown if and to which extent biological correlates for AN might be present in individuals without clinical AN symptomatology. We therefore investigated the contribution of polygenic load for AN on body weight and prefrontal brain structure in a sample of n = 380 nonclinical individuals. A polygenic score (PGS) reflecting the individual genetic load for the trait of anorexia nervosa was calculated. Structural MRI data were acquired and preprocessed using the cortical parcellation stream of FreeSurfer. We observed a significant PGS × sex interaction effect on body mass index (BMI), which was driven by a negative correlation between PGS and BMI in female participants. Imaging analyses revealed significant interaction effects of sex × PGS on surface area of the lateral orbitofrontal cortex (OFC), the pars orbitalis (PO), the rostral middle frontal gyrus (RMF) and the pars triangularis (PT) of the left frontal cortex. The interaction effects were driven by positive correlations between PGS and prefrontal surface areas in female participants and negative correlations in male participants. We furthermore found sex-specific associations between BMI and left RMF surface area as well as between BMI and left PO and left RMF thickness. Our findings demonstrate a sex-specific association between polygenic load for AN, BMI, and prefrontal brain structure in nonclinical individuals. Hence, this study identifies structural abnormalities associated with polygenic load for AN and BMI in brain regions deeply involved in behavioral inhibition and impulse regulation as candidate brain regions for future research.

Latent resting-state network dynamics in boys and girls with attention-deficit/hyperactivity disorder.

Neuroimaging studies of subjects with ADHD typically show altered functional connectivity in prefrontal, striatal, and several temporal brain regions. While the majority of studies have focused on connectivity that is averaged over time, we investigated the temporal dynamics of brain network changes in resting-state fMRI. Using the ADHD-200 consortium, we characterized the time course of latent state changes using Hidden Markov Modeling, and compared state changes between boys and girls with ADHD along with typically developing controls. Sex differences were found in latent state switching, with boys dwelling longer in a given state than girls, and concurrently having fewer overall state transitions. These sex differences were found in children with ADHD and in typically developing controls. Children with ADHD were also found to be more variable in terms of state transitions than controls. These findings add to the growing literature on neural sex differences and may be related to the sex difference in focal versus diffuse attention.

Theta-burst transcranial magnetic stimulation induced functional connectivity changes between dorsolateral prefrontal cortex and default-mode-network.

Functional connectivity (FC) is fundamental to brain function and has been implicated in many neuropsychological and neuropsychiatric disorders. It is then of great scientific and clinical interest to find a non-invasive approach to modulate FC. Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulational tool that can affect the target region and remote brain areas. While the distributed effects of TMS are postulated to be through either structural or functional connectivity, an understudied but of great scientific interest question is whether TMS can change the FC between these regions. The purpose of this study was to address this question in normal healthy brain using TMS with continuous theta burst stimulation (cTBS) pulses, which are known to have long-lasting inhibition function. FC was calculated from resting state fMRI before and after real and control (SHAM) stimulation. Compared to SHAM, the repetitive TMS (rTMS) reduces FC between the cTBS target: the left dorsolateral prefrontal cortex (lDLPFC) and brain regions within the default mode network (DMN), proving the effects of rTMS on FC. The reduction of FC might be the results of the inhibitory effects of cTBS rTMS.

Relational thinking in later adulthood.

The research addressed the role of relational processing capacity in cognitive aging focusing on (a) age-differences in complex relational processing, (b) the domain-generality of complex relational processing, and (c) associations of complex relational processing with other processes. Participants were 125 adults in three groups with mean ages of 30.55 (younger), 53.43 (middle), and 74.41 years (older). Each relational processing task (sentence comprehension, n-term premise integration, Latin square) included items at three complexity levels. Accuracy was lower on more complex items and relational complexity had a greater effect in the older group. Confirmatory factor analyses confirmed a single complex relational processing factor, consistent with a domain-general capacity. Relational processing was related to other executive processes. This relationship was stronger in the older than younger and middle groups, possibly reflecting dedifferentiation or neural noise. In structural models with planning (Tower of London) and class reasoning as outcome variables, complex relational processing had a significant impact (β = .455, p < .001 and β = .661, p < .001, respectively) over and above age, processing speed, working memory, task switching, response inhibition, and Stroop interference. In the structural model with fluid intelligence (matrix reasoning) as the outcome variable, age had a significant impact (β = -.222, p < .001), over and above all other variables, suggesting that the processes underpinning age-related declines in matrix reasoning are more diverse than those assessed in the current research. Complex relational processing is an important factor in cognitive aging, possibly reflecting its reliance on prefrontal brain regions. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

P60-F Emotional modulation of ERPs elicited by angry faces in patients with schizotypal disorder and schizophrenia

Background Emotion recognition is distorted in schizophrenia. The schizotypal disorder can be considered a mild form of schizophrenia, sharing some features but showing better preservation of prefrontal brain regions. We studied the differences in visual ERPs elicited by neutral and angry faces in patients with schizophrenia and schizotypal disorder. Materials and methods Only male participants took part in our study: 18 patients with paranoid schizophrenia, 17 patients with the schizotypal disorder, and 50 healthy volunteers. Participants had to push different buttons for photographs of neutral and angry/aggressive people (total of 80). We recorded 128-channel EEG and analyzed the evoked brain activity elicited by faces and facial expressions. The difference (p Results EM was observed at early latencies in all groups in group-specific locations. EM in components N170, N250, and P280 was quite similar in scalp topography for controls and schizotypal disorder, while it was not observed in schizophrenia for N170 and N250. The central distribution of EM was found for N450 component in all groups, and for the later latencies, EM with similar topography was found only in controls and in schizotypal disorder. Conclusions Our results indicate that EM in schizotypal disorder exhibits a general resemblance with EM in healthy controls at the latencies longer than 130 Presumably, certain stages of facial expression processing are preserved in schizotypal disorder. At the earlier latencies, the EM in schizotypal disorder has more in common with schizophrenia than with healthy controls.

Stress and prospective memory: What is the role of cortisol?

Studies investigating effects of acute stress on Prospective Memory (PM) so far yielded heterogeneous findings. Although results were commonly attributed to stress-induced changes in cortisol, past research did not disentangle effects of cortisol from the effects of sympathetic nervous system (SNS) activation and cognitive reappraisal. The present study therefore aimed at investigating the mere effect of cortisol on PM tasks that differently involve prefrontal brain regions (nonfocal vs. focal PM tasks) via a placebo-controlled oral pharmacological intake of 10 mg hydrocortisone mimicking physiological responses to stress. Contrary to our prediction, enhanced levels of cortisol did not affect PM accuracy and monitoring costs, neither for the focal nor the nonfocal PM tasks. These results suggest that changes of cortisol levels do not underlie potential stress effects on PM. Further exploratory results revealed that PM performance was higher in the 3 pm than in the 1 pm placebo group. This means that PM performance, independently of effects of cortisol, seem to vary throughout the day.

The Shifting Architecture of Cognition and Brain Function in Older Adulthood

Cognitive aging is often described in the context of loss or decline. Emerging research suggests that the story is more complex, with older adults showing both losses and gains in cognitive ability. With increasing age, declines in controlled, or fluid, cognition occur in the context of gains in crystallized knowledge of oneself and the world. This inversion in cognitive capacities, from greater reliance on fluid abilities in young adulthood to increasingly crystallized or semanticized cognition in older adulthood, has profound implications for cognitive and real-world functioning in later life. The shift in cognitive architecture parallels changes in the functional network architecture of the brain. Observations of greater functional connectivity between lateral prefrontal brain regions, implicated in cognitive control, and the default network, implicated in memory and semantic processing, led us to propose the default-executive coupling hypothesis of aging. In this review we provide evidence that these changes in the functional architecture of the brain serve as a neural mechanism underlying the shifting cognitive architecture from younger to older adulthood. We incorporate findings spanning cognitive aging and cognitive neuroscience to present an integrative model of cognitive and brain aging, describing its antecedents, determinants, and implications for real-world functioning.

Reversing working memory decline in the elderly.

Noninvasive delivery of alternating electrical currents to temporal and prefrontal brain regions improves working memory and reverses age-related changes in brain dynamics in the elderly, report Reinhart and Nguyen in this issue of Nature Neuroscience. They also report a similar effect in young adults with poor working memory performance.

Research round-up

The genetic foundations of depressive disorders are highlighted in a study by Howard and colleagues. Researchers included data from three GWAS studies in a meta-analysis of data from 246 363 individuals with depression and 561 190 controls. The analysis identified 102 independent variants associated with depression (p<5 × 10−8). After testing in a replication cohort of 414 055 individuals with depression and 892 299 controls, 87 of the 102 variants remained significant (α=0·05/102; p<4·90 × 10−4). Genetic overlap with 41 other behavioural and disease traits was found, (false discovery rate p<0·01), some of which were seemingly novel genetic correlations, including associations between depression and age at menopause (rG=−0·11 [SE 0·03]) and depression and Crohn's disease (rG=0·09 [0·03]). Interpreting the results from gene-set and enrichment analysis, the authors noted the potential role of prefrontal brain regions in depression.

Looking into the Brain of Buridan’s Ass

To survive, animals must maximize the minimum-take care of the least satisfied among their basic needs. In this issue of Neuron, a study by Juechems etal. (2019) illustrates that this core principle might shape the way medial prefrontal regions of the human brain drive and valuate sequential choices between different types of reward.

The self and depression: Four psychological theories and their potential neural correlates.

We review theory and research pertaining to psychodynamic, social, humanistic, and ethological models of the self and depression and examine research into the neurobiological bases of the self and depression. We provide a narrative review of classic and recent empirical evidence pertaining to these four models of the relation of the self to depression as well as exemplar relevant neurobiological research. Evidence stemming from each of the four theories reviewed here shows a robust relationship between deficits in the sense of self and depressive symptoms, as well as increases in depressive symptoms over time. A smaller body of literature has linked one's sense of self to onsets of depressive episodes. A growing body of literature has linked self-relevant variables to functioning in various prefrontal and cortical midline brain regions as well as emotion and reward processing brain regions which have in turn been linked to depression. Evidence has therefore converged across all four theories and confirmed that a deficit in one's sense of self confers risk for depression and that there is substantial overlap in the brain areas associated with one's sense of self and depression.

Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions.

Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.

Sex-Specific Associations Between Inter-Individual Differences in Heart Rate Variability and Inter-Individual Differences in Emotion Regulation.

Neurobiological theories suggest that inter-individual differences in vagally mediated heart rate variability (vmHRV) have the potential to serve as a biomarker for inter-individual differences in emotion regulation that are due to inter-individual differences regarding the engagement of prefrontal and (para-)limbic brain regions during emotion processing. To test these theories, we investigated whether inter-individual differences in vmHRV would be associated with inter-individual differences in emotion regulation. We determined resting state vmHRV in a sample of 176 individuals that had also completed a short self-report measure of reappraisal and suppression use. Resting state vmHRV was derived from short-term (300 s) and ultra-short-term (120 s, 60 s) recordings of participants’ heart rate to determine the robustness of possible findings. Irrespective of recording length, we found that an increase in resting state vmHRV was associated with an increase in self-reported reappraisal but not suppression use. However, this association was only evident among male but not female participants, indicating a sex-specific association between inter-individual differences in resting state vmHRV and inter-individual differences in self-reported emotion regulation. These findings, which are consistent with previous ones, support theoretical claims that inter-individual differences in vmHRV serve as a biomarker for inter-individual differences in emotion regulation. Combing (ultra-)short-term measures of resting state vmHRV with short self-report measures of emotion regulation may, thus, be useful for researchers who have to investigate the neurobiological mechanisms of emotion regulation in a time- and resource-efficient manner.

Stimulating Self-Regulation: A Review of Non-invasive Brain Stimulation Studies of Goal-Directed Behavior.

Self-regulation enables individuals to guide their thoughts, feelings, and behaviors in a purposeful manner. Self-regulation is thus crucial for goal-directed behavior and contributes to many consequential outcomes in life including physical health, psychological well-being, ethical decision making, and strong interpersonal relationships. Neuroscientific research has revealed that the prefrontal cortex plays a central role in self-regulation, specifically by exerting top-down control over subcortical regions involved in reward (e.g., striatum) and emotion (e.g., amygdala). To orient readers, we first offer a methodological overview of tDCS and then review experiments using non-invasive brain stimulation techniques (especially transcranial direct current stimulation) to target prefrontal brain regions implicated in self-regulation. We focus on brain stimulation studies of self-regulatory behavior across three broad domains of response: persistence, delay behavior, and impulse control. We suggest that stimulating the prefrontal cortex promotes successful self-regulation by altering the balance in activity between the prefrontal cortex and subcortical regions involved in emotion and reward processing.

Transcranial Direct Current Stimulation in Psychiatry: What Psychiatrists Need to Know.

Transcranial direct current stimulation (tDCS) is emerging as a potential treatment for a host of neuropsychiatric disorders. Data appear to indicate that tDCS applied over frontal or prefrontal brain regions may reduce symptoms of major depression, yet results have been mixed. Early studies showed promise, but recent work failed to replicate earlier results. The decision whether to use tDCS is further affected by the complex regulatory environment; no tDCS devices are cleared by the U.S. Food and Drug Administration for clinical use. Older systems have grandfathered regulatory approval for treating mood, anxiety, and insomnia, although they have not demonstrated efficacy in rigorous trials. Furthermore, as the field of noninvasive brain stimulation advances, various side effects and contraindications are increasingly recognized. Over the last few years, research and consumer use of tDCS have outpaced education, thus providing little guidance for clinicians and trainees about how to understand tDCS. Therefore, this focused review includes those items psychiatric clinicians and trainees most need to understand tDCS, including basic electrical and neurophysiological principles, a brief review of efficacy data in major depressive disorder, and suggested guidelines about how to manage patients using tDCS.

Prenatal ethanol exposure and enkephalinergic neurotransmission.

Endogenous opioids (enkephalins, endorphins and dynorphins) are small peptides that play a main role in pain perception and analgesia, as well as in alcohol (ethanol) reinforcement and reward. Alcohol reinforcement involves the ethanol-induced activation of the endogenous opioid system, a process that may augment the hedonic value and the reinforcing properties of the drug, which in turn increases substance consumption. Changes in opioidergic transmission may contribute to alcohol intoxication and to the neuroadaptive responses produced by the long-lasting exposure to ethanol. Opioidergic transmission may be altered by ethanol at distinct levels, including the expression of precursor mRNAs, biosynthesis and release of opioid peptides, as well as ligand binding to opioid receptors. In adult rats, β-endorphinergic and enkephalinergic transmission, through activation of mu and delta opioid receptors, mediate ethanol reinforcement and high alcohol drinking behavior. Prenatal ethanol exposure (PEE) selectively modifies Methionine-enkephalin (Met-enk) content in several brain regions of infant and adolescent rats, particularly those of the reward circuits. In preweanling rats, Met-enk content is decreased in the ventral tegmental area but is increased in the prefrontal cortex and the nucleus accumbens and other brain areas, as a consequence of a short and moderate ethanol exposure during late gestation. PEE also increases Met-enk levels in the prefrontal cortex and other brain regions of 30-day-old adolescent rats. These findings suggest that mesocorticolimbic enkephalins are essential in ethanol reinforcement in offspring, as previously reported in adult rats.

The frontal cortex is a heart-brake: Reduction in delta oscillations is associated with heart rate deceleration

Prefrontal brain regions have been proposed to modulate vagally mediated heart rate variability (HRV) through their action on subcortical structures. This study aimed at investigating the beat-to-beat influence of the brain cortex over the heart through a high temporal resolution estimation of brain-heart coupling. Electrocardiogram (ECG) and electroencephalogram (EEG) from 32 scalp positions were recorded at rest for 5 min in 38 participants. To assess beat-to-beat cortical control on vagal activity, the longest and shortest inter-beat intervals (IBIs) were identified for each participant. Then, the EEG activity was time-locked to R waves in the ECG signal and analyzed using a time-frequency approach. Logistic regression models were applied to predict the trial-by-trial occurrence of long and short IBIs from cardiac-related EEG activity. Delta power reduction over prefrontal and frontocentral areas preceding the R-wave increased the probability for a long IBI to occur, as compared to a short one. Moreover, reduced prefrontal delta power preceding the R wave was correlated to higher cardiac vagal control, as reflected by the High Frequency (HF) power of HRV calculated on the whole recording time. The present results support the hypothesis that phasic activation/deactivation of prefrontal areas modulates vagal control of heart rate at rest.

Prediction of the response to repetitive transcranial magnetic stimulation by spectral powers of prefrontal regions of brain.

Introduction: Quantitative assessments of the effects induced by repetitive transcranial magnetic stimulation (rTMS) are crucial to develop more efficient and personalized treatments. Objectives: To determine the spectral powers of different subbands of EEG correlated with treatment response to rTMS. Materials and Methods: the spectral powers of different subbands of EEG correlated with treatment response to rTMS. Methods: In an open label study 10 patients with intractable major depression received a ten session 20 Hz rTMS over left dorsolateral prefrontal cortex. The EEGs were recorded in all subjects prior and post intervention using a 19-channel EEG system. Hamilton depression rating scale (HAM-D) was also used to determine treatment response. The rTMS protocol consisted of daily one session of 60 trains (2.5 s, inter-train of 17.5 s) at 120% MT for 5 consecutive days per week and 2 weeks. Absolute and relative powers in all electrodes for delta (0-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), sensorimotor rhythm (SMR)(12-15 Hz), beta (15-20 HZ), and high beta (20-28 Hz) were compared prior and post intervention in the responders. Spectral powers of prefrontal and sensorimotor regions of brain predict response to repetitive transcranial magnetic stimulation Results: In the responders (n=5), absolute powers of alpha in F3, F4, C3, and C4 electrodes, absolute power of theta and alpha sub-bands in C4 electrode significantly changed (P<0.05). In the SMR band, absolute powers in the Fp1, Fp2, F3, F4, F7, FZ, C3, and C4 significantly changed (P<0.05). In beta subband, relative power in C4 and absolute power in Fp1, Fp2, F4, CZ, and C4 significantly changed (P < 0.05). Conclusion: The spectral powers of particular sub-bands in prefrontal cortex and sensorimotor areas can predict response to rTMS treatment.

Weakened Functional Connectivity Between the Amygdala and the Ventromedial Prefrontal Cortex Is Longitudinally Related to Psychopathic Traits in Low-Income Males During Early Adulthood.

Psychopathy is a complex disorder comprised of harmful personality traits and impulsive-lifestyle and antisocial behaviors. Weakened functional connectivity between limbic and prefrontal brain regions is thought to underlie impaired sensitivity to others' emotions that contribute to the interpersonal and affective personality traits associated with psychopathy. We tested whether weakened functional connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC) during the processing of fearful, angry, and neutral facial expressions, was prospectively related to psychopathic traits in early adulthood. The sample included 167 low-income, racially diverse, urban males who completed an fMRI scan at age 20 and questionnaire measures at ages 20 and 22. Weakened amygdala-vmPFC functional connectivity to fearful, but not neutral or angry, faces at age 20 was related to higher psychopathic traits at age 22.