Dorsal Anterior Cingulate Research Articles

Brain mechanisms of rumination and negative self-referential processing in adolescent depression

BackgroundDepression is linked to cognitive biases towards more negative and less positive self-relevant information. Rumination, perseverative negative thinking about the past and the self, may contribute to these biases. Methods159 adolescents (12–18 years), with a range of depression symptoms, completed the SRET during fMRI. Multiple regressions tested associations between conventional self-report and ecological momentary assessment (EMA) measured rumination, and neural and behavioral responses during a self-referent encoding task (SRET). ResultsHigher rumination (conventional self-report and EMA) was associated with more negative and fewer positive words endorsed and recalled. Higher self-reported (but not EMA) rumination was associated with higher accuracy in recognizing negative words and greater insula and dorsal anterior cingulate activity to negative versus positive words. LimitationsThe sample included mostly non-Hispanic White participants with household incomes above the national average, highlighting the need for replication in more diverse samples. Word endorsement discrepancies required fMRI analyses to model neural response to viewing negative versus positive words. ConclusionsAdolescents with higher rumination endorsed and recalled more negative and fewer positive words and recognized more negative words during the SRET. Higher insula reactivity, a key region for modulating externally-oriented attention and internally-oriented self-referential processes, may contribute to links between rumination and negative memory biases. These findings provide insight into neurocognitive mechanisms underlying depression.

Dorsal Anterior Cingulate Cortex Coordinates Contextual Mental Imagery for Single-Beat Manipulation during Rhythmic Sensorimotor Synchronization.

Flexible pulse-by-pulse regulation of sensorimotor synchronization is crucial for voluntarily showing rhythmic behaviors synchronously with external cueing; however, the underpinning neurophysiological mechanisms remain unclear. We hypothesized that the dorsal anterior cingulate cortex (dACC) plays a key role by coordinating both proactive and reactive motor outcomes based on contextual mental imagery. To test our hypothesis, a missing-oddball task in finger-tapping paradigms was conducted in 33 healthy young volunteers. The dynamic properties of the dACC were evaluated by event-related deep-brain activity (ER-DBA), supported by event-related potential (ERP) analysis and behavioral evaluation based on signal detection theory. We found that ER-DBA activation/deactivation reflected a strategic choice of motor control modality in accordance with mental imagery. Reverse ERP traces, as omission responses, confirmed that the imagery was contextual. We found that mental imagery was updated only by environmental changes via perceptual evidence and response-based abductive reasoning. Moreover, stable on-pulse tapping was achievable by maintaining proactive control while creating an imagery of syncopated rhythms from simple beat trains, whereas accuracy was degraded with frequent erroneous tapping for missing pulses. We conclude that the dACC voluntarily regulates rhythmic sensorimotor synchronization by utilizing contextual mental imagery based on experience and by creating novel rhythms.

Closed-Loop Infraslow Brain-Computer Interface can Modulate Cortical Activity and Connectivity in Individuals With Chronic Painful Knee Osteoarthritis: A Secondary Analysis of a Randomized Placebo-Controlled Clinical Trial.

Introduction. Chronic pain is a percept due to an imbalance in the activity between sensory-discriminative, motivational-affective, and descending pain-inhibitory brain regions. Evidence suggests that electroencephalography (EEG) infraslow fluctuation neurofeedback (ISF-NF) training can improve clinical outcomes. It is unknown whether such training can induce EEG activity and functional connectivity (FC) changes. A secondary data analysis of a feasibility clinical trial was conducted to determine whether EEG ISF-NF training can significantly alter EEG activity and FC between the targeted cortical regions in people with chronic painful knee osteoarthritis (OA). Methods. A parallel, two-arm, double-blind, randomized, sham-controlled clinical trial was conducted. People with chronic knee pain associated with OA were randomized to receive sham NF training or source-localized ratio ISF-NF training protocol to down-train ISF bands at the somatosensory (SSC), dorsal anterior cingulate (dACC), and uptrain pregenual anterior cingulate cortices (pgACC). Resting state EEG was recorded at baseline and immediate post-training. Results. The source localization mapping demonstrated a reduction (P = .04) in the ISF band activity at the left dorsolateral prefrontal cortex (LdlPFC) in the active NF group. Region of interest analysis yielded significant differences for ISF (P = .008), slow (P = .007), beta (P = .043), and gamma (P = .012) band activities at LdlPFC, dACC, and bilateral SSC. The FC between pgACC and left SSC in the delta band was negatively correlated with pain bothersomeness in the ISF-NF group. Conclusion. The EEG ISF-NF training can modulate EEG activity and connectivity in individuals with chronic painful knee osteoarthritis, and the observed EEG changes correlate with clinical pain measures.

Switching tinnitus on or off: An initial investigation into the role of the pregenual and rostral to dorsal anterior cingulate cortices

Research indicates that hearing loss significantly contributes to tinnitus, but it alone does not fully explain its occurrence, as many people with hearing loss do not experience tinnitus. To identify a secondary factor for tinnitus generation, we examined a unique dataset of individuals with intermittent chronic tinnitus, who experience fluctuating periods of tinnitus. EEGs of healthy controls were compared to EEGs of participants who reported perceiving tinnitus on certain days, but no tinnitus on other days.. The EEG data revealed that tinnitus onset is associated with increased theta activity in the pregenual anterior cingulate cortex and decreased theta functional connectivity between the pregenual anterior cingulate cortex and the auditory cortex. Additionally, there is increased alpha effective connectivity from the dorsal anterior cingulate cortex to the pregenual anterior cingulate cortex. When tinnitus is not perceived, differences from healthy controls include increased alpha activity in the pregenual anterior cingulate cortex and heightened alpha connectivity between the pregenual anterior cingulate cortex and auditory cortex. This suggests that tinnitus is triggered by a switch involving increased theta activity in the pregenual anterior cingulate cortex and decreased theta connectivity between the pregenual anterior cingulate cortex and auditory cortex, leading to increased theta-gamma cross-frequency coupling, which correlates with tinnitus loudness. Increased alpha activity in the dorsal anterior cingulate cortex correlates with distress. Conversely, increased alpha activity in the pregenual anterior cingulate cortex can transiently suppress the phantom sound by enhancing theta connectivity to the auditory cortex. This mechanism parallels chronic neuropathic pain and suggests potential treatments for tinnitus by promoting alpha activity in the pregenual anterior cingulate cortex and reducing alpha activity in the dorsal anterior cingulate cortex through pharmacological or neuromodulatory approaches.

Myo-inositol Levels in the Dorsal Anterior Cingulate Cortex Predicts Anxiety-to-Eat in Anorexia Nervosa.

Anorexia nervosa (AN) is a mental and behavioral health condition characterized by an intense fear of weight or fat gain, severe restriction of food intake resulting in low body weight, and distorted self-perception of body shape or weight. While substantial research has focused on general anxiety in AN, less is known about eating-related anxiety and its underlying neural mechanisms. Therefore, we sought to characterize anxiety-to-eat in AN and examine the neurometabolic profile within the dorsal anterior cingulate cortex (dACC), a brain region putatively involved in magnifying the threat response. Women seeking inpatient treatment for AN and women of healthy weight without a lifetime history of an eating disorder (healthy controls; HC) completed a computer-based behavioral task assessing anxiety-to-eat in response to images of higher (HED) and lower (LED) energy density foods. Participants also underwent magnetic resonance spectroscopy of the dACC in a 3 Tesla scanner. The AN group reported greater anxiety to eat HED and LED foods relative to the HC group. Both groups reported greater anxiety to eat HED foods relative to LED foods. The neurometabolite myo-inositol (mI) was lower in the dACC in AN relative to HC, and mI levels negatively predicted anxiety to eat HED but not LED foods in the AN group only. mI levels in the dACC were independent of body weight, body mass, and general anxiety. These findings provide critical new insight into the clinically challenging feature and underlying neural mechanisms of eating-related anxiety and indicate mI levels in the dACC could serve as a novel biomarker of illness severity that is independent of body weight to identify individuals vulnerable to disordered eating or eating pathology as well as a potential therapeutic target.

The neurocomputational link between defensive cardiac states and approach-avoidance arbitration under threat.

Avoidance, a hallmark of anxiety-related psychopathology, often comes at a cost; avoiding threat may forgo the possibility of a reward. Theories predict that optimal approach-avoidance arbitration depends on threat-induced psychophysiological states, like freezing-related bradycardia. Here we used model-based fMRI analyses to investigate whether and how bradycardia states are linked to the neurocomputational underpinnings of approach-avoidance arbitration under varying reward and threat magnitudes. We show that bradycardia states are associated with increased threat-induced avoidance and more pronounced reward-threat value comparison (i.e., a stronger tendency to approach vs. avoid when expected reward outweighs threat). An amygdala-striatal-prefrontal circuit supports approach-avoidance arbitration under threat, with specific involvement of the amygdala and dorsal anterior cingulate (dACC) in integrating reward-threat value and bradycardia states. These findings highlight the role of human freezing states in value-based decision making, relevant for optimal threat coping. They point to a specific role for amygdala/dACC in state-value integration under threat.

Mapping Early Brain-Body Interactions: Associations of Fetal Heart Rate Variation with Newborn Brainstem, Hypothalamic, and Dorsal Anterior Cingulate Cortex Functional Connectivity.

The autonomic nervous system (ANS) regulates the body's physiology, including cardiovascular function. As the ANS develops during the second to third trimester, fetal heart rate variability (HRV) increases while fetal heart rate (HR) decreases. In this way, fetal HR and HRV provide an index of fetal ANS development and future neurobehavioral regulation. Fetal HR and HRV have been associated with child language ability and psychomotor development behavior in toddlerhood. However, their associations with postbirth autonomic brain systems, such as the brainstem, hypothalamus, and dorsal anterior cingulate cortex (dACC), have yet to be investigated even though brain pathways involved in autonomic regulation are well established in older individuals. We assessed whether fetal HR and HRV were associated with the brainstem, hypothalamic, and dACC functional connectivity in newborns. Data were obtained from 60 pregnant individuals (ages 14-42) at 24-27 and 34-37 weeks of gestation using a fetal actocardiograph to generate fetal HR and HRV. During natural sleep, their infants (38 males and 22 females) underwent a fMRI scan between 40 and 46 weeks of postmenstrual age. Our findings relate fetal heart indices to brainstem, hypothalamic, and dACC connectivity and reveal connections with widespread brain regions that may support behavioral and emotional regulation. We demonstrated the basic physiologic association between fetal HR indices and lower- and higher-order brain regions involved in regulatory processes. This work provides the foundation for future behavioral or physiological regulation research in fetuses and infants.

Out-of-phase transcranial alternating current stimulation modulates the neurodynamics of inhibitory control

Transcranial alternating current stimulation (tACS) is an efficient neuromodulation technique that enhances cognitive function in a non-invasive manner. Using functional magnetic resonance imaging, we investigated whether tACS with different phase lags (0° and 180°) between the dorsal anterior cingulate and left dorsolateral prefrontal cortices modulated inhibitory control performance during the Stroop task. We found out-of-phase tACS mediated improvements in task performance, which was neurodynamically reflected as putamen, dorsolateral prefrontal, and primary motor cortical activation as well as prefrontal-based top-down functional connectivity. Our observations uncover the neurophysiological bases of tACS-phase-dependent neuromodulation and provide a feasible non-invasive approach to effectively modulate inhibitory control.

359 Low-Intensity Focused Ultrasound to Human Dorsal Anterior Cingulate Cortex and Insula Attenuates Measures of Central Sensitization

INTRODUCTION: Central sensitization is the abnormal amplified response to pain and is associated with chronic pain. Increased insula and dorsal anterior cingulate cortex (dACC) activity is associated with central sensitization. Low-intensity focused ultrasound (LIFU) is a novel form of non-invasive neuromodulation that can precisely target the anterior insula (AI), posterior insula (PI) and dACC. METHODS: N = 18 healthy participants underwent conditioned pain modulation (CPM) and temporal summation of pain (TSP) tasks before and after 10 minutes of LIFU or sham stimulations. For CPM, the conditioning stimulus (CS) was a cold pressor test to the left hand and the test stimulus (TS) was a brief transient heat stimulus to the dorsum of the right hand. For TSP, 10 transient heat stimuli (>0.33 Hz) were administered to the dorsum of the right hand. The primary outcome measure for both tasks was perceived pain ratings (0-9). Electrodermal response and electrocardiogram was collected to evaluate the effect of LIFU on autonomic reactivity. RESULTS: LIFU to PI increased CPM 0.5 ± 0.181 compared to sham (p = 0.024). LIFU to PI also significantly reduced perceived pain during the TSP task compared to sham (p < 0.001). We also found a significant difference between dACC and sham conditions during TSP by -0.55 ± 0.05 (p < 0.001). LIFU to the AI increases frequency domain measures of heart-rate variability. CONCLUSIONS: LIFU to the insula and dACC affects pain processing in measures of central sensitization. This demonstrates the neuromodulation abilities of LIFU and is a promising tool to develop noninvasive clinical therapies for chronic pain conditions.

Breath Gas Markers in Depression and Their Relationship with Brain Metabolism

IntroductionDysfunctional changes in the glutamatergic system play an important role in the pathophysiology of depression. Glutamate regulates various neuronal function, such as nerve migration, excitability, plasticity, as well as long-term potentiation and long-term synaptic depression. Failures in this process might cause emotional/cognitive changes associated with stress-induced depressive symptoms, a part of our current understanding of the pathophysiology of depression. These changes might be related to deviations in biochemical blood parameters, but also to volatile organic compounds (VOCs) measured in breath.Objectives1) To replicate our previous finding that concentration of volatile organic compounds in expiratory breath gas and metabolites derived from MR spectroscopy distinguish unmedicated depressed patients from healthy participants, (2) to determine whether the amount of these VOCs is associated with severity of depression and anxiety, and (3) to correlate breath-VOC-content with glutamatergic neurotransmission and energy metabolism derived from MR spectroscopy.Methods25 antidepressant-free patients with major depression according to DSM V (18-65 years of age) are recruited from our out- and inpatient clinics. The controls will consist of 25 healthy age-and-sex-matched participants. Breath gas analyses will be carried out at awakening, and 30 and 60 minutes thereafter, and at 5pm using PTR-TOF-MS with direct on time measurement through a special sampler. A 7 Tesla Siemens Terra MRI scanner will be used to undertake spectroscopic measurements. Concentrations of glutamate and β-hydroxybutyrate levels in the pregenual and dorsal anterior cingulate gyrus will subsequently be assessed.ResultsStatistical analysis for differences between groups corrected for multiple measurements will be carried out. Concentration of VOCs will be correlated with brain metabolism and severity of symptoms.ConclusionsVOCs in breath are proposed to be an efficient and non-invasive marker for depression-related biochemical changes related to disease severity, and eventually useful for personalized treatment planning.Disclosure of InterestNone Declared

Asymmetry in political polarization at multiple levels of bias

AbstractWhile some studies show ideological asymmetry in outgroup bias between rightists and leftists, those studies often target an ideologically biased outgroup. Here, we bypass this issue by targeting the ideological outgroups (rightists for leftists, and leftists for rightists). We rely on a magnetoencephalography‐based approach delineating function‐specific neural mechanisms to test for ideological asymmetries at multiple levels: explicit psychological self‐reports, implicit behavioral bias, and neural oscillations. Using a computational model balancing the stimuli and screening 81 rightists and leftist Israeli individuals, we find ideological asymmetry with rightists being more biased at all three levels. Furthermore, the neural results add important insights by uncovering two underlying mechanisms: The first (late beta‐band motor activity) is strongly associated with implicit behavior, while the second (early alpha‐band dorsal anterior cingulate activity) reveal an antileftist bias for both groups. We discuss implications of the findings on bias, ideological asymmetry, their neural underpinnings, and social norms.

Sex differences in alcohol's effects on fronto-amygdalar functional connectivity during processing of emotional stimuli.

Amygdala function underlying emotion processing has been shown to vary with an individuals' biological sex. Expanding upon functional magnetic resonance imaging (fMRI) findings reported previously where a low level of response was the focus, we examined alcohol and sex effects on functional connectivity between the amygdala and other brain regions. The central hypothesis predicted that sex would influence alcohol's effects on frontal-limbic functional circuits underlying the processing of negative and positive facial emotions. Secondary analyses were conducted on data from a double-blind, placebo controlled, within-subjects, cross-over study in 54 sex-matched pairs (N = 108) of 18- to 25-year-old individuals without an alcohol use disorder at baseline. Participants performed an emotional faces fMRI processing task after placebo or approximately 0.7 mL/kg of ethanol. Psychophysiological interaction analyses examined functional connectivity between the amygdala with other brain regions. There were significant alcohol-by-sex interactions when processing negatively valenced faces. Whereas intoxicated men exhibited decreased functional connectivity between the amygdala and ventral and dorsal anterior cingulate, angular gyrus, and middle frontal gyrus connectivity was increased in intoxicated women. There was also a main sex effect where women exhibited less functional connectivity in the middle insula than men regardless of whether they received alcohol or placebo. For happy faces, main effects of both sex and alcohol were observed. Women exhibited less amygdala functional connectivity in the right inferior frontal gyrus than men. Both men and women exhibited greater functional connectivity in the superior frontal gyrus in response to alcohol than placebo. Alcohol's effects on amygdala functional circuits that underlying emotional processing vary by sex. Women had higher functional connectivity than men following exposure to a moderate dose of alcohol which could indicate that women arebetter than men at processing affectively laden stimuli when intoxicated.

Neuroscience of Hypnosis: A Neurophysiological View of Hypnotherapy

Objective: This narrative literature review is intended to briefly clarify the history and concepts of hypnosis, history, scientific advancement in the field and therapeutic applications. The theme will have greater contextualization regarding the neurophysiology of hypnosis. Methods: In this bibliographic review (databases, websites and specialized journals) studies were selected seeking as keywords "Hypnosis", "Neurobiology", "Hypnotic Response", "Historical", "Research", to approach these concepts in the clinical area and research in the health area, in order to seek greater grounding on the concepts and neurobiological mechanisms involved in hypnotherapy. The databases evaluated were MEDLINE, GOOGLE ACADEMIC, PUBMED, SCIENCE DIRECT, SciELO and LILACS. Results: In the selected studies on the theme, the concepts on hypnotherapy and history are addressed. Hypnosis, recognized as a psychobiological process, modifies brain activity, affecting areas such as sensory cortexes, the dorsal anterior cingulate gyrus, and the prefrontal cortex. This neurocognitive alteration influences perception, making hypnosis an effective tool in the modulation of various clinical conditions in a way that complements conventional therapy. Conclusion: The neurophysiology of hypnosis is a field in constant evolution. Although the exact understanding of the neurophysiological processes underlying hypnosis is not yet fully understood, advances in neuroscience reveal insights into the hypnotic response. The progress in new neuroimaging technologies and methodologies may provide clearer answers about the mechanisms involved in hypnotherapy, as well as proving the effectiveness of its application.

Prefrontal signals precede striatal signals for biased credit assignment in motivational learning biases

Actions are biased by the outcomes they can produce: Humans are more likely to show action under reward prospect, but hold back under punishment prospect. Such motivational biases derive not only from biased response selection, but also from biased learning: humans tend to attribute rewards to their own actions, but are reluctant to attribute punishments to having held back. The neural origin of these biases is unclear. Specifically, it remains open whether motivational biases arise primarily from the architecture of subcortical regions or also reflect cortical influences, the latter being typically associated with increased behavioral flexibility and control beyond stereotyped behaviors. Simultaneous EEG-fMRI allowed us to track which regions encoded biased prediction errors in which order. Biased prediction errors occurred in cortical regions (dorsal anterior and posterior cingulate cortices) before subcortical regions (striatum). These results highlight that biased learning is not a mere feature of the basal ganglia, but arises through prefrontal cortical contributions, revealing motivational biases to be a potentially flexible, sophisticated mechanism.

Intraoperative changes in large-scale thalamic circuitry following laser ablation of hypothalamic hamartomas

Background and objectivesGelastic seizures due to hypothalamic hamartomas (HH) are challenging to treat, in part due to an incomplete understanding of seizure propagation pathways. Although magnetic resonance imaging-guided laser interstitial thermal therapy (MRgLITT) is a promising intervention to disconnect HH from ictal propagation networks, the optimal site of ablation to achieve seizure freedom is not known. In this study, we investigated intraoperative post-ablation changes in resting-state functional connectivity to identify large-scale networks associated with successful disconnection of HH. MethodsChildren who underwent MRgLITT for HH at two institutions were consecutively recruited and followed for a minimum of one year. Seizure freedom was defined as Engel score of 1A at the last available follow-up. Immediate pre- and post- ablation resting-state functional MRI scans were acquired while maintaining a constant depth of general anesthetic. Multivariable generalized linear models were used to identify intraoperative changes in large-scale connectivity associated with seizure outcomes. ResultsTwelve patients underwent MRgLITT for HH, five of whom were seizure-free at their last follow-up. Intraprocedural changes in thalamocortical circuitry involving the anterior cingulate cortex were associated with seizure-freedom. Children who were seizure-free demonstrated an increase and decrease in connectivity to the pregenual and dorsal anterior cingulate cortices, respectively. In addition, children who became seizure-free demonstrated increased thalamic connectivity to the periaqueductal gray immediately following MRgLITT. DiscussionSuccessful disconnection of HH is associated with intraoperative, large-scale changes in thalamocortical connectivity. These changes provide novel insights into the large-scale basis of gelastic seizures and may represent intraoperative biomarkers of treatment success.

4 Resting State Functional Connectivity Impairments Implicate CNS Mechanisms Underlying Chronic Pain and Depression in Gulf War Veterans’ Illness

Objective:Around 200,000 veterans (up to 32% of those deployed) of the 1991 Gulf War (GW) suffer from GW veterans’ illness (GWVI). GWVI is a poorly understood chronic medical condition, characterized by symptoms indicative of brain function deficits in multiple domains. Among the symptoms of brain impairment GWVI-related chronic headaches and body muscle and joint pain conditions (GWVI-HAP) are the most debilitating, affecting around 64% of the GWVI veterans. Further, depression carries a very high co-morbid rate (>50%) in patients with chronic pain, including GWVI-HAP. In this preliminary study, we examined the integrity of brain function networks in a group of GWI-HAP veterans, with resting state fMRI (rsfMRI).Participants and Methods:Data from the first twenty-two GWVI-HAP veterans from two ongoing parallel clinical trials was examined. Of these 14 subjects (GWVI-HAP-DM) had mild depression (Hamilton Rating Scale for Depression (HSRD < 13); and 8 subjects (GWVI-HAP-DS) had moderate to severe depression (HSRD > 14). Written informed consent was obtained from all participants in the protocol approved by the local Institutional Review Board. RsfMRI data was acquired on a Siemens 3T Prisma-Fit MRI scanner using a 10-minute whole-brain high resolution simultaneous multi-slice (SMS) gradient echo echo-planar imaging (EPI) sequence: TR/TE/FA = 2.2 sec/ 27 msec/80°, and analyzed with well-established image processing pipelines. Functional connectivity (FC) to different regions implicated in depression and chronic pain was assessed with seed-based correlation analysis. Between group differences in FC were obtained with 2-sample t-tests.Results:GWVI-HAP-DS group exhibited significantly (p < 0.05) reduced FC compared to GWVI-HAP-DM between frontal lobe (medial (mPFC), and dorsolateral (dlPFC) prefrontal cortex) and the striatum. This indicates that malfunction of fronto-striatal circuits could be a source of the increased chronic pain and depression seen in veterans with GWVI- HAP-DS. Dysregulation of fronto-striatal networks has been implicated in major depressive disorder as well as many chronic pain conditions. In addition, FC between mPFC, and salience network (SN; anterior insula and dorsal anterior cingulate) and limbic (subgenual and ventral anterior cingulate) regions were also reduced in GWVI-HAP-DS. Similarly, mPFC and SN also exhibited reduced FC to pain processing regions (posterior insula, centromedian thalamus and cerebellum). These FC impairments could reflect greater deficits in regulation of and salience attribution to emotions and nociception in the GWVI-HAP-DS group. Finally, GWVI-HAP-DS also exhibited reduced FC between nodes of the default mode network. DMN impairments also have been observed in many depressive and chronic pain conditions.Conclusions:The results of this preliminary analysis implicate impairments in cognitive control of emotion and nociception as a mechanism underlying the enhanced chronic pain and depression observed in GWVI-HAP veterans, especially those with moderate to severe depression. A fuller picture of deficits in FC in brain function networks is expected to emerge as more GWI-HAP subjects of both groups along with age matched healthy controls are examined in this ongoing project. Better understanding of impairments in these networks in GWI-HAP will benefit the rehabilitation of veterans with GWI-HAP.

EEG synchronized left prefrontal transcranial magnetic stimulation (TMS) for treatment resistant depression is feasible and produces an entrainment dependent clinical response: A randomized controlled double blind clinical trial

BackgroundSynchronizing a TMS pulse with a person's underlying EEG rhythm can modify the brain's response. It is unclear if synchronizing rTMS trains might boost the antidepressant effect of TMS. In this first-in-human trial, we demonstrated that a single TMS pulse over the prefrontal cortex produces larger effects in the anterior cingulate depending on when it is fired relative to the individual's EEG alpha phase. Objective/hypothesesWe had three hypotheses. 1) It is feasible to synchronize repetitive TMS (rTMS) delivery to a person's preferred prefrontal alpha phase in each train of every session during a 30-visit TMS depression treatment course. 2) EEG-synchronized rTMS would produce progressive entrainment greater than unsynchronized (UNSYNC) rTMS. And 3) SYNC TMS would have better antidepressant effects than UNSYNC (remission, final Hamilton Depression Rating <10). MethodsWe enrolled (n = 34) and treated (n = 28) adults with treatment resistant depression (TRD) and randomized them to receive six weeks (30 treatments) of left prefrontal rTMS at their individual alpha frequency (IAF) (range 6–13 Hz). Prior to starting the clinical trial, all patients had an interleaved fMRI-EEG-TMS (fET) scan to determine which phase of their alpha rhythm would produce the largest BOLD response in their dorsal anterior cingulate. Our clinical EEG-rTMS system then delivered the first TMS pulse in each train time-locked to this patient-specific ‘preferred phase’ of each patient's left prefrontal alpha oscillation. We randomized patients (1:1) to SYNC or UNSYNC, and all were treated at their IAF. Only the SYNC patients had the first pulse of each train for all sessions synchronized to their individualized preferred alpha phase (75 trains/session ×30 sessions, 2250 synchronizations per patient over six weeks). The UNSYNC group used a random firing with respect to the alpha wave. All other TMS parameters were balanced between the two groups.The system interfaced with a MagStim Horizon air-cooled Fig. 8 TMS coil. All patients were treated at their IAF, coil in the F3 position, 120 % MT, frequency 6–13 Hz, 40 pulses per train, average 15-s inter-train interval, 3000 pulses per session. All patients, raters, and treaters were blinded. ResultsIn the intent to treat (ITT) sample, both groups had significant clinical improvement from baseline with no significant between-group differences, with the USYNC group having mathematically more remitters but fewer responders. (ITT -15 SYNC; 13 UNSYNC, response 5 (33 %), 1 (7 %), remission 2 (13 %), 6 (46 %). The same was true with the completer sample - 12 SYNC; 12 UNSYNC, response 4, 4 (both 30 %), remission 2 (17 %), 3 (25 %)). The clinical EEG phase synchronization system performed well with no failures. The average treatment session was approximately 90 min, with 30 min for placing the EEG cap and the actual TMS treatment for 45 min (which included gathering 10 min of resting EEG). Four subjects (1 SYNC) withdrew before six weeks of treatment. All 24 completer patients were treated for six weeks despite the trial occurring during the COVID pandemic. SYNC patients exhibited increased post-stimulation EEG entrainment over the six weeks. A detailed secondary analysis of entrainment data in the SYNC group showed that responders and non-responders in this group could be cleanly separated based on the total number of sessions with entrainment and the session-to-session precision of the entrained phase. For the SYNC group only, depression improvement was greater when more sessions were entrained at similar phases. ConclusionsSynchronizing prefrontal TMS with a patient's prefrontal alpha frequency in a blinded clinical trial is possible and produces progressive EEG entrainment in synchronized patients only. There was no difference in overall clinical response in this small clinical trial. A secondary analysis showed that the consistency of the entrained phase across sessions was significantly associated with response outcome only in the SYNC group. These effects may not simply be due to how the stimulation is delivered but also whether the patient's brain can reliably entrain to a precise phase. EEG-synchronized clinical delivery of TMS is feasible and requires further study to determine the best method for determining the phase for synchronization.

Aberrant resting-state functional connectivity of the globus pallidus interna in first-episode schizophrenia.

The striatal-pallidal pathway plays an important role in cognitive control and modulation of behaviors. Globus pallidus interna (GPi), as a primary output structure, is crucial in modulating excitation and inhibition. Studies of GPi in psychiatric illnesses are lacking given the technical challenges of examining this small and functionally diverse subcortical structure. 71 medication-naïve first episode schizophrenia (FES) participants and 73 healthy controls (HC) were recruited at the Shanghai Mental Health Center. Clinical symptoms and imaging data were collected at baseline and, in a subset of patients, 8weeks after initiating treatment. Resting-state functional connectivity of sub-regions of the GP were assessed using a novel mask that combines two atlases to create 8 ROIs in the GP. Baseline imaging data from 63 FES patients and 55 HC met quality standards and were analyzed. FES patients exhibited less negative connectivity and increased positive connectivity between the right anterior GPi and several cortical and subcortical areas at baseline compared to HC (PFWE<0.05). Positive functional connectivity between the right anterior GPi and several brain areas, including the right dorsal anterior cingulate gyrus, was associated with severity of positive symptoms (PFWE<0.05) and predicted treatment response after 8weeks (n=28, adjusted R2=0.486, p<0.001). Our results implicate striatal-pallidal-thalamic pathways in antipsychotic efficacy. If replicated, these findings may reflect failure of neurodevelopmental processes in adolescence and early adulthood that decrease functional connectivity as an index of failure of the limbic/associative GPi to appropriately inhibit irrelevant signals in psychosis.

Neuroimaging Insights: Kava's (Piper methysticum) Effect on Dorsal Anterior Cingulate Cortex GABA in Generalized Anxiety Disorder.

Generalised Anxiety Disorder (GAD) is a prevalent, chronic mental health disorder. The measurement of regional brain gamma-aminobutyric acid (GABA) offers insight into its role in anxiety and is a potential biomarker for treatment response. Research literature suggests Piper methysticum (Kava) is efficacious as an anxiety treatment, but no study has assessed its effects on central GABA levels. This study investigated dorsal anterior cingulate (dACC) GABA levels in 37 adult participants with GAD. GABA was measured using proton magnetic resonance spectroscopy (1H-MRS) at baseline and following an eight-week administration of Kava (standardised to 120 mg kavalactones twice daily) (n = 20) or placebo (n = 17). This study was part of the Kava for the Treatment of GAD (KGAD; ClinicalTrials.gov: NCT02219880), a 16-week intervention study. Compared with the placebo group, the Kava group had a significant reduction in dACC GABA (p = 0.049) at eight weeks. Baseline anxiety scores on the HAM-A were positively correlated with GABA levels but were not significantly related to treatment. Central GABA reductions following Kava treatment may signal an inhibitory effect, which, if considered efficacious, suggests that GABA levels are modulated by Kava, independent of reported anxiety symptoms. dACC GABA patterns suggest a functional role of higher levels in clinical anxiety but warrants further research for symptom benefit. Findings suggest that dACC GABA levels previously un-examined in GAD could serve as a biomarker for diagnosis and treatment response.

Developmental Neuroimaging of Cognitive Flexibility: Update and Future Directions

Cognitive flexibility, or the ability to mentally switch between tasks according to changing environmental demands, supports optimal life outcomes, making it an important executive function to study across development. Here we review the literature examining the development of cognitive flexibility, with an emphasis on studies using task-based functional magnetic resonance imaging (fMRI). The neuroimaging literature suggests that key brain regions important for cognitive flexibility include the inferior frontal junction and regions within the midcingulo-insular network, including the insular and dorsal anterior cingulate cortices. We further discuss challenges surrounding studying cognitive flexibility during neurodevelopment, including inconsistent terminology, the diversity of fMRI task paradigms, difficulties with isolating cognitive flexibility from other executive functions, and accounting for developmental changes in cognitive strategy. Future directions include assessing how developmental changes in brain network dynamics enable cognitive flexibility and examining potential modulators of cognitive flexibility including physical activity and bilingualism.