Does attachment in adolescence predict neural responses to handholding in adulthood? A functional magnetic resonance imaging study.

Objective: Early life experiences, including attachment-related experiences, inform internal working models that guide adult relationship behaviors. Few studies have examined the association between adolescent attachment and adult relationship behavior on a neural level. The current study examined attachment in adolescence and its associations with neural correlates of relationship behaviors in adulthood. Method: 85 participants completed the Adult Attachment Interview (AAI) at age 14. Ten years later, at age 24, participants underwent functional brain image when participants were under the threat of electric shock alone, holding the hand of a stranger, or their partner. Results: We found that adolescents who were securely attached at age 14 showed increased activation in regions commonly associated with cognitive, affective, and reward processing when they held the hand of their partner and stranger compared to being alone. Adolescents with higher preoccupied attachment scores showed decreased activation in similar regions only during the stranger handholding condition compared to being alone. Conclusions: These findings suggest that adolescent attachment predicts adult social relationship behaviors on a neural level, in regions largely consistent with previous literature. Broadly, this study has implications for understanding long-term links between attachment and adult relationship behaviors and has potential for informing intervention.

Predicting performance in attention by measuring key metabolites in the PCC with 7T MRS.

The posterior cingulate cortex (PCC) is a key hub of the default mode network and is known to play an important role in attention. Using ultra-high field 7 Tesla magnetic resonance spectroscopy (MRS) to quantify neurometabolite concentrations, this exploratory study investigated the effect of the concentrations of myo-inositol (Myo-Ins), glutamate (Glu), glutamine (Gln), aspartate or aspartic acid (Asp) and gamma-amino-butyric acid (GABA) in the PCC on attention in forty-six healthy participants. Each participant underwent an MRS scan and cognitive testing, consisting of a trail-making test (TMT A/B) and a test of attentional performance. After a multiple regression analysis and bootstrapping for correction, the findings show that Myo-Ins and Asp significantly influence (p < 0.05) attentional tasks. On one hand, Myo-Ins shows it can improve the completion times of both TMT A and TMT B. On the other hand, an increase in aspartate leads to more mistakes in Go/No-go tasks and shows a trend towards enhancing reaction time in Go/No-go tasks and stability of alertness without signal. No significant (p > 0.05) influence of Glu, Gln and GABA was observed.

Region-specific Cerebral Metabolic Alterations in Parkinson's Disease Patients With/without Mild Cognitive Impairment.

N-acetylaspartate (NAA), choline (Cho) and creatine (Cr) are brain metabolites involved in some key neuronal functions within the brain, such as cognitive function. The aim of this study was to investigate whether Parkinson's disease (PD) with different cognitive status induces regional brain metabolite differences. 38 diagnosed PD patients, including 18 PD patients with normal cognitive (PDN), 20 PD subjects with cognitive impairment (PDMCI) and 25 healthy controls (HC) participated in this study. All subjects underwent a single-voxel proton MR spectroscopy (1H-MRS) on a 3T scanner. 1H-MRS were obtained from bilateral PCC, left thalamus and PFC regions in all subjects, respectively. Region-specific cerebral metabolic alterations existed in PD patients with different cognitive status. PDMCI patients showed a significant reduction of NAA, Cho and tCr in the PCC and left thalamus, compared to healthy controls; whereas lower levels of NAA and Cho in thalamus were found in PDN patients. Moreover, Cho and tCr levels were positively correlated with MMSE scores. Both NAA and tCr in PCC levels were positively correlated with MMSE and MoCA scores. The combination of thalamic and PCC metabolites showed a 75.6% accuracy in distinguishing PDMCI patients from PDN patients. This study provides preliminary evidence that thalamic, PCC and PFC neurometabolic alterations occur in PD patients with cognition decline. Findings of this study indicate that NAA and tCr abnormalities in PCC and thalamus might be used as a biomarker to track cognitive decline in Parkinson's disease in clinical settings.

Functional connectivity of the posterior cingulate cortex in autism spectrum disorder.

The purpose of this study was to assess the functional connectivity of the posterior cingulate cortex in autism spectrum disorder (ASD). We used resting-state functional magnetic resonance imaging (rsfMRI) brain scans of adolescents diagnosed with ASD and a neurotypical control group. The Autism Brain Imaging Data Exchange (ABIDE) consortium was utilized to acquire data from the University of Michigan (145 subjects) and data from the New York University (183 subjects). The posterior cingulate cortex showed reduced connectivity with the anterior cingulate cortex for the ASD group compared to the control group. These two brain regions have previously both been linked to ASD symptomology. Specifically, the posterior cingulate cortex has been associated with behavioral control and executive functions, which appear to be responsible for the repetitive and restricted behaviors (RRB) in ASD. Our findings support previous data indicating a neurobiological basis of the disorder, and the specific functional connectivity changes involving the posterior cingulate cortex and anterior cingulate cortex may be a potential neurobiological biomarker for the observed RRBs in ASD.

Dynamical changes of interaction across functional brain communities during propofol-induced sedation.

It is crucial to understand how anesthetics disrupt information transmission within the whole-brain network and its hub structure to gain insight into the network-level mechanisms underlying propofol-induced sedation. However, the influence of propofol on functional integration, segregation, and community structure of whole-brain networks were still unclear. We recruited 12 healthy subjects and acquired resting-state functional magnetic resonance imaging data during 5 different propofol-induced effect-site concentrations (CEs): 0, 0.5, 1.0, 1.5, and 2.0 µg/ml. We constructed whole-brain functional networks for each subject under different conditions and identify community structures. Subsequently, we calculated the global and local topological properties of whole-brain network to investigate the alterations in functional integration and segregation with deepening propofol sedation. Additionally, we assessed the alteration of key nodes within the whole-brain community structure at each effect-site concentrations level. We found that global participation was significantly increased at high effect-site concentrations, which was mediated by bilateral postcentral gyrus. Meanwhile, connector hubs appeared and were located in posterior cingulate cortex and precentral gyrus at high effect-site concentrations. Finally, nodal participation coefficients of connector hubs were closely associated to the level of sedation. These findings provide valuable insights into the relationship between increasing propofol dosage and enhanced functional interaction within the whole-brain networks.

Modulation of hippocampal theta oscillations via deep brain stimulation of the parietal cortex depends on cognitive state.

The angular gyrus (AG) and posterior cingulate cortex (PCC) demonstrate extensive structural and functional connectivity with the hippocampus and other core recollection network regions. Consequently, recent studies have explored neuromodulation targeting these and other regions as a potential strategy for restoring function in memory disorders such as Alzheimer's Disease. However, determining the optimal approach for neuromodulatory devices requires understanding how parameters like selected stimulation site, cognitive state during modulation, and stimulation duration influence the effects of deep brain stimulation (DBS) on electrophysiological features relevant to episodic memory. We report experimental data examining the effects of high-frequency stimulation delivered to the AG or PCC on hippocampal theta oscillations during the memory encoding (study) or retrieval (test) phases of an episodic memory task. Results showed selective enhancement of anterior hippocampal slow theta oscillations with stimulation of the AG preferentially during memory retrieval. Conversely, stimulation of the PCC attenuated slow theta oscillations. We did not observe significant behavioral effects in this (open-loop) stimulation experiment, suggesting that neuromodulation strategies targeting episodic memory performance may require more temporally precise stimulation approaches.

Functionality of arousal-regulating brain circuitry at rest predicts human cognitive abilities.

Arousal state is regulated by subcortical neuromodulatory nuclei, such as locus coeruleus, which send wide-reaching projections to cortex. Whether higher-order cortical regions have the capacity to recruit neuromodulatory systems to aid cognition is unclear. Here, we hypothesized that select cortical regions activate the arousal system, which, in turn, modulates large-scale brain activity, creating a functional circuit predicting cognitive ability. We utilized the Human Connectome Project 7T functional magnetic resonance imaging dataset (n = 149), acquired at rest with simultaneous eye tracking, along with extensive cognitive assessment for each subject. First, we discovered select frontoparietal cortical regions that drive large-scale spontaneous brain activity specifically via engaging the arousal system. Second, we show that the functionality of the arousal circuit driven by bilateral posterior cingulate cortex (associated with the default mode network) predicts subjects' cognitive abilities. This suggests that a cortical region that is typically associated with self-referential processing supports cognition by regulating the arousal system.

Intrinsic connectivity demonstrates a shared role of the posterior cingulate for cue reactivity in both gambling and cocaine use disorders.

Cue reactivity is relevant across addictive disorders as a process relevant to maintenance, relapse, and craving. Understanding the neurobiological foundations of cue reactivity across substance and behavioral addictions has important implications for intervention development. The present study used intrinsic connectivity distribution methods to examine functional connectivity during a cue-exposure fMRI task involving gambling, cocaine and sad videos in 22 subjects with gambling disorder, 24 with cocaine use disorder, and 40 healthy comparison subjects. Intrinsic connectivity distribution implicated the posterior cingulate cortex (PCC) at a stringent whole-brain threshold. Post-hoc analyses investigating the nature of the findings indicated that individuals with gambling disorder and cocaine use disorder exhibited decreased connectivity in the posterior cingulate during gambling and cocaine cues, respectively, as compared to other cues and compared to other groups. Brain-related cue reactivity in substance and behavioral addictions involve PCC connectivity in a content-to-disorder specific fashion. The findings suggesting that PCC-related circuitry underlies cue reactivity across substance and behavioral addictions suggests a potential biomarker for targeting in intervention development.

Micro-RNA profiles of pathology and resilience in posterior cingulate cortex of cognitively intact elders.

The posterior cingulate cortex (PCC) is a key hub of the default mode network underlying autobiographical memory retrieval, which falters early in the progression of Alzheimer's disease (AD). We recently performed RNA sequencing of post-mortem PCC tissue samples from 26 elderly Rush Religious Orders Study participants who came to autopsy with an ante-mortem diagnosis of no cognitive impairment but who collectively displayed a range of Braak I-IV neurofibrillary tangle stages. Notably, cognitively unimpaired subjects displaying high Braak stages may represent cognitive resilience to AD pathology. Transcriptomic data revealed elevated synaptic and ATP-related gene expression in Braak Stages III/IV compared with Stages I/II, suggesting these pathways may be related to PCC resilience. We also mined expression profiles for small non-coding micro-RNAs (miRNAs), which regulate mRNA stability and may represent an underexplored potential mechanism of resilience through the fine-tuning of gene expression within complex cellular networks. Twelve miRNAs were identified as differentially expressed between Braak Stages I/II and III/IV. However, the extent to which the levels of all identified miRNAs were associated with subject demographics, neuropsychological test performance and/or neuropathological diagnostic criteria within this cohort was not explored. Here, we report that a total of 667 miRNAs are significantly associated (rho > 0.38, P < 0.05) with subject variables. There were significant positive correlations between miRNA expression levels and age, perceptual orientation and perceptual speed. By contrast, higher miRNA levels correlated negatively with semantic and episodic memory. Higher expression of 15 miRNAs associated with lower Braak Stages I-II and 47 miRNAs were associated with higher Braak Stages III-IV, suggesting additional mechanistic influences of PCC miRNA expression with resilience. Pathway analysis showed enrichment for miRNAs operating in pathways related to lysine degradation and fatty acid synthesis and metabolism. Finally, we demonstrated that the 12 resilience-related miRNAs differentially expressed in Braak Stages I/II versus Braak Stages III/IV were predicted to regulate mRNAs related to amyloid processing, tau and inflammation. In summary, we demonstrate a dynamic state wherein differential PCC miRNA levels are associated with cognitive performance and post-mortem neuropathological AD diagnostic criteria in cognitively intact elders. We posit these relationships may inform miRNA transcriptional alterations within the PCC relevant to potential early protective (resilience) or pathogenic (pre-clinical or prodromal) responses to disease pathogenesis and thus may be therapeutic targets.

Functionality of arousal-regulating brain circuitry at rest predicts human cognitive abilities.

Arousal state is regulated by subcortical neuromodulatory nuclei, such as locus coeruleus, which send wide-reaching projections to cortex. Whether higher-order cortical regions have the capacity to recruit neuromodulatory systems to aid cognition is unclear. Here, we hypothesized that select cortical regions activate the arousal system, which in turn modulates large-scale brain activity, creating a functional circuit predicting cognitive ability. We utilized the Human Connectome Project 7T functional magnetic resonance imaging dataset (N=149), acquired at rest with simultaneous eye tracking, along with extensive cognitive assessment for each subject. First, we discovered select frontoparietal cortical regions that drive large-scale spontaneous brain activity specifically via engaging the arousal system. Second, we show that the functionality of the arousal circuit driven by bilateral posterior cingulate cortex (associated with the default mode network) predicts subjects' cognitive abilities. This suggests that a cortical region that is typically associated with self-referential processing supports cognition by regulating the arousal system.

Posterior cingulate cortex hyperactivity in conversion disorder: a PET/MRI study.

Introduction: Several neuroimaging studies have been conducted to demonstrate the specific structural and functional brain correlations of conversion disorder. Although the findings of neuroimaging studies are not consistent, when evaluated as a whole, they suggest the presence of significant brain abnormalities. The aim of this study is to investigate brain metabolic activity through F-18 fluorodeoxyglucose PET/MRI in order to shed light on the neural correlates of conversion disorder. Methods: 20 patients diagnosed with conversion disorder were included in the study. Hamilton Depression and Anxiety Rating Scales, Somatosensory Amplification Scale and Somatoform Dissociation Scale were administered. Then, brain F-18 FDG-PET/MRI was performed.. Results: Hypermetabolism was found in posterior cingulate R, while glucose metabolisms of other brain regions were observed to be within the normal limits. When compared with the control group, statistically significant differences in z-scores were observed among all brain regions except for parietal superior R and cerebellum. No correlation was observed between the metabolisms of the left ACC and left medial PFC; left ACC and left temporal lateral cortex; cerebellum and left parietal inferior cortex despite the presence of positive correlations between these regions in the opposite hemisphere. Discussion: Results of the study suggest a potential involvement of the DMN which is associated with arousal and self-referential processing as well as regions associated with motor intention and self-agency.

Dual role of α7 nicotinic acetylcholine receptors in the retrosplenial cortex for aversive memory acquisition and retrieval.

In the retrosplenial cortex (RSC), the role of cholinergic modulation via α7 nicotinic receptors and their involvement in memory is unknown. In recent years, the RSC has been shown to deteriorate in the early stages of Alzheimer's disease (AD). Likewise, the cholinergic system has been postulated as one of those responsible for cognitive impairment in patients with AD. Great interest has arisen in the study of α7 nicotinic receptors as more specific targets for the treatment of this disease. For this reason, we aim to study the role of α7 receptors of the RSC in memory processing. We infused a selective α7 receptor antagonist into the anterior part of the RSC (aRSC) to assess its role in different phases of aversive memory processing using an inhibitory avoidance task. We found that α7 nicotinic receptors are involved in memory acquisition and expression, but not in its consolidation. These results identify aRSC α7 nicotinic receptors as key players in aversive memory processing and highlight their significant potential as therapeutic targets for Alzheimer's disease.

Continuous inhalation of essential oil increases gray matter volume.

Research into the health benefits of scents is on the rise. However, little is known about the effects of continuous inhalation, such as wearing scents on clothing, on brain structure. Therefore, in this study, an intervention study was conducted on a total of 50 healthy female people, 28 in the intervention group and 22 in the control group, asking them to wear a designated rose scent on their clothes for a month. The effect of continuous inhalation of essential oil on the gray matter of the brain was measured by calculating changes in brain images of participants taken before and after the intervention using Magnetic Resonance Imaging (MRI). The results showed that the intervention increased the gray matter volume (GMV) of the whole brain and posterior cingulate cortex (PCC) subregion. On the other hand, the GMV of the amygdala and orbitofrontal cortex (OFC) did not change. This study is the first to show that continuous scent inhalation changes brain structure.

Motor performance and functional connectivity between the posterior cingulate cortex and supplementary motor cortex in bipolar and unipolar depression.

Although implicated in unsuccessful treatment, psychomotor deficits and their neurobiological underpinnings in bipolar (BD) and unipolar (UD) depression remain poorly investigated. Here, we hypothesized that motor performance deficits in depressed patients would relate to basal functional coupling of the hand primary motor cortex (M1) and the posterior cingulate cortex (PCC) with the supplementary motor area (SMA). We performed a longitudinal, naturalistic study in BD, UD and matched healthy controls comprising of two resting-state functional MRI measurements five weeks apart and accompanying assessments of motor performance using a finger tapping task (FTT). A subject-specific seed-based analysis describing functional connectivity between PCC-SMA as well as M1-SMA was conducted. The basal relationships with motor performance were investigated using linear regression models and all measures were compared across groups. Performance in FTT was impaired in BD in comparison to HC in both sessions. Behavioral performance across groups correlated significantly with resting state functional coupling of PCC-SMA, but not of M1-SMA regions. This relationship was partially reflected in a reduced PCC-SMA connectivity in BD vs HC in the second session. Exploratory evaluation of large-scale networks coupling (SMN-DMN) exhibited no correlation to motor performance. Our results shed new light on the association between the degree of disruption in the SMA-PCC anticorrelation and the level of motor impairment in BD.

Glucose metabolism in posterior cingulate cortex has supplementary value to predict the progression of cognitively unimpaired to dementia due to Alzheimer's disease: an exploratory study of 18F-FDG-PET.

Amyloid-ß (Aß) and tau are important biomarkers to predict the progression of cognitively unimpaired (CU) to dementia due to Alzheimer's disease (AD), according to the diagnosis framework from the US National Institute on Aging and the Alzheimer's Association (NIA-AA). However, it is clinically difficult to predict those subjects who were already with Aß positive (A +) or tau positive (T +). As a typical characteristic of neurodegeneration in the diagnosis framework, the hypometabolism of the posterior cingulate cortex (PCC) has significant clinical value in the early prediction and prevention of AD. In this paper, we proposed the glucose metabolism in the PCC as a biomarker supplement to Aß and tau biomarkers. First, we calculated the standard uptake value ratio (SUVR) of PCC based on fluorodeoxyglucose positron emission computed tomography (FDG PET) imaging. Secondly, we performed Kaplan-Meier (KM) survival analyses to explore the predictive performance of PCC SUVR, and the hazard ratio (HR) was calculated. Finally, we performed Pearson correlation analyses to explore the physiological significance of PCC SUVR. As a result, the PCC SUVR showed a consistent downward trend along the AD continuum. KM analyses showed better predictive performance when we combined PCC SUVR with cerebro-spinal fluid (CSF) Aß42 (from HR = 2.56 to 3.00 within 5 years; from HR = 2.76 to 4.20 within 10 years) and ptau-181 (from 2.83 to 3.91 within 5 years; from HR = 2.32 to 4.17 within 10 years). There was a slight correlation between Aß42/Aß40 and PCC SUVR (r = 0.14, p = 0.02). In addition, several cognition scales were also correlated to PCC SUVR (from r = -0.407 to 0.383, p < 0.05). Our results showed that glucose metabolism in PCC may be a potential biomarker supplement to the Aß and tau biomarkers to predict the progression of CU to AD.

A tale of two targets: examining the differential effects of posterior cingulate cortex- and amygdala-targeted fMRI-neurofeedback in a PTSD pilot study.

Introduction: Real-time fMRI-based neurofeedback (rt-fMRI-NFB) is a non-invasive technology that enables individuals to self-regulate brain activity linked to neuropsychiatric symptoms, including those associated with post-traumatic stress disorder (PTSD). Selecting the target brain region for neurofeedback-mediated regulation is primarily informed by the neurobiological characteristics of the participant population. There is a strong link between PTSD symptoms and multiple functional disruptions in the brain, including hyperactivity within both the amygdala and posterior cingulate cortex (PCC) during trauma-related processing. As such, previous rt-fMRI-NFB studies have focused on these two target regions when training individuals with PTSD to regulate neural activity. However, the differential effects of neurofeedback target selection on PTSD-related neural activity and clinical outcomes have not previously been investigated. Methods: Here, we compared whole-brain activation and changes in PTSD symptoms between PTSD participants (n = 28) that trained to downregulate activity within either the amygdala (n = 14) or the PCC (n = 14) while viewing personalized trauma words. Results: For the PCC as compared to the amygdala group, we observed decreased neural activity in several regions implicated in PTSD psychopathology - namely, the bilateral cuneus/precuneus/primary visual cortex, the left superior parietal lobule, the left occipital pole, and the right superior temporal gyrus/temporoparietal junction (TPJ) - during target region downregulation using rt-fMRI-NFB. Conversely, for the amygdala as compared to the PCC group, there were no unique (i.e., over and above that of the PCC group) decreases in neural activity. Importantly, amygdala downregulation was not associated with significantly improved PTSD symptoms, whereas PCC downregulation was associated with reduced reliving and distress symptoms over the course of this single training session. In this pilot analysis, we did not detect significant between-group differences in state PTSD symptoms during neurofeedback. As a critical control, the PCC and amygdala groups did not differ in their ability to downregulate activity within their respective target brain regions. This indicates that subsequent whole-brain neural activation results can be attributed to the effects of the neurofeedback target region selection in terms of neurophysiological function, rather than as a result of group differences in regulatory success. Conclusion: In this study, neurofeedback-mediated downregulation of the PCC was differentially associated with reduced state PTSD symptoms and simultaneous decreases in PTSD-associated brain activity during a single training session. This novel analysis may guide researchers in choosing a neurofeedback target region in future rt-fMRI-NFB studies and help to establish the clinical efficacy of specific neurofeedback targets for PTSD. A future multi-session clinical trial of rt-fMRI-NFB that directly compares between PCC and amygdala target regions is warranted.

Sleep Deficits Inter-Link Lower Basal Forebrain-Posterior Cingulate Connectivity and Perceived Stress and Anxiety Bidirectionally in Young Men.

BACKGROUND: The basal nucleus of Meynert (BNM), a primary source of cholinergic projections to the cortex, plays key roles in regulating the sleep-wake cycle and attention. Sleep deficit is associated with impairment in cognitive and emotional functions. However, whether or how cholinergic circuit, sleep, and cognitive/emotional dysfunction are inter-related remains unclear. METHODS: We curated the Human Connectome Project data and explored BNM resting state functional connectivities (rsFC) in relation to sleep deficit, based on the Pittsburgh Sleep Quality Index (PSQI), cognitive performance, and subjective reports of emotional states in 687 young adults (342 women). Imaging data were processed with published routines and evaluated at a corrected threshold. We assessed the correlation between BNM rsFC, PSQI, and clinical measurements with Pearson regressions and their inter-relationships with mediation analyses. RESULTS: In whole-brain regressions with age and alcohol use severity as covariates, men showed lower BNM rsFC with the posterior cingulate cortex (PCC) in correlation with PSQI score. No clusters were identified in women at the same threshold. Both BNM-PCC rsFC and PSQI score were significantly correlated with anxiety, perceived stress, and neuroticism scores in men. Moreover, mediation analyses showed that PSQI score mediated the relationship between BNM-PCC rsFC and these measures of negative emotions bidirectionally in men. CONCLUSIONS: Sleep deficit is associated with negative emotions and lower BNM rsFC with the PCC. Negative emotional states and BNM-PCC rsFC are bidirectionally related through poor sleep quality. These findings are specific to men, suggesting potential sex differences in the neural circuits regulating sleep and emotional states.

Increased cerebral lactate levels in adults with autism spectrum disorders compared to non-autistic controls: a magnetic resonance spectroscopy study.

INTRODUCTION: Autism spectrum disorder (ASD) encompasses a heterogeneous group with varied phenotypes and etiologies. Identifying pathogenic subgroups could facilitate targeted treatments. One promising avenue is investigating energy metabolism, as mitochondrial dysfunction has been implicated in a subgroup of ASD. Lactate, an indicator of energy metabolic anomalies, may serve as a potential biomarker for this subgroup. This study aimed to examine cerebral lactate (Lac+) levels in high-functioning adults with ASD, hypothesizing elevated mean Lac+ concentrations in contrast to neurotypical controls (NTCs). MATERIALS AND METHODS: Magnetic resonance spectroscopy (MRS) was used to study cerebral Lac+ in 71 adults with ASD and NTC, focusing on the posterior cingulate cortex (PCC). After quality control, 64 ASD and 58 NTC participants remained. Lac+ levels two standard deviations above the mean of the control group were considered elevated. RESULTS: Mean PCC Lac+ levels were significantly higher in the ASD group than in the NTC group (p = 0.028; Cohen's d = 0.404), and 9.4% of the ASD group had elevated levels as compared to 0% of the NTCs (p = 0.029). No significant correlation was found between blood serum lactate levels and MRS-derived Lac+ levels. LIMITATIONS: A cautious interpretation of our results is warranted due to a p value of 0.028. In addition, a higher than anticipated proportion of data sets had to be excluded due to poor spectral quality. CONCLUSION: This study confirms the presence of elevated cerebral Lac+ levels in a subgroup of adults with ASD, suggesting the potential of lactate as a biomarker for mitochondrial dysfunction in a subgroup of ASD. The lower-than-expected prevalence (20% was expected) and moderate increase require further investigation to elucidate the underlying mechanisms and relationships with mitochondrial function.

Early-in-life isoflurane exposure alters resting-state functional connectivity in juvenile non-human primates.

BACKGROUND: Clinical studies suggest that anaesthesia exposure early in life affects neurobehavioural development. We designed a non-human primate (NHP) study to evaluate cognitive, behavioural, and brain functional and structural alterations after isoflurane exposure during infancy. These NHPs displayed decreased close social behaviour and increased astrogliosis in specific brain regions, most notably in the amygdala. Here we hypothesise that resting-state functional connectivity MRI can detect alterations in connectivity of brain areas that relate to these social behaviours and astrogliosis. METHODS: Imaging was performed in 2-yr-old NHPs under light anaesthesia, after early-in-life (postnatal days 6-12) exposure to 5 h of isoflurane either one or three times, or to room air. Brain images were segmented into 82 regions of interest; the amygdala and the posterior cingulate cortex were chosen for a seed-based resting-state functional connectivity MRI analysis. RESULTS: We found differences between groups in resting-state functional connectivity of the amygdala and the auditory cortices, medial premotor cortex, and posterior cingulate cortex. There were also alterations in resting-state functional connectivity between the posterior cingulate cortex and secondary auditory, polar prefrontal, and temporal cortices, and the anterior insula. Relationships were identified between resting-state functional connectivity alterations and the decrease in close social behaviour and increased astrogliosis. CONCLUSIONS: Early-in-life anaesthesia exposure in NHPs is associated with resting-state functional connectivity alterations of the amygdala and the posterior cingulate cortex with other brain regions, evident at the juvenile age of 2 yr. These changes in resting-state functional connectivity correlate with the decrease in close social behaviour and increased astrogliosis. Using resting-state functional connectivity MRI to study the neuronal underpinnings of early-in-life anaesthesia-induced behavioural alterations could facilitate development of a biomarker for anaesthesia-induced developmental neurotoxicity.

Signatures of Electrical Stimulation Driven Network Interactions in the Human Limbic System.

Stimulation-evoked signals are starting to be used as biomarkers to indicate the state and health of brain networks. The human limbic network, often targeted for brain stimulation therapy, is involved in emotion and memory processing. Previous anatomic, neurophysiological, and functional studies suggest distinct subsystems within the limbic network (Rolls, 2015). Studies using intracranial electrical stimulation, however, have emphasized the similarities of the evoked waveforms across the limbic network. We test whether these subsystems have distinct stimulation-driven signatures. In eight patients (four male, four female) with drug-resistant epilepsy, we stimulated the limbic system with single-pulse electrical stimulation. Reliable corticocortical evoked potentials (CCEPs) were measured between hippocampus and the posterior cingulate cortex (PCC) and between the amygdala and the anterior cingulate cortex (ACC). However, the CCEP waveform in the PCC after hippocampal stimulation showed a unique and reliable morphology, which we term the "limbic Hippocampus-Anterior nucleus of the thalamus-Posterior cingulate, HAP-wave." This limbic HAP-wave was visually distinct and separately decoded from the CCEP waveform in ACC after amygdala stimulation. Diffusion MRI data show that the measured end points in the PCC overlap with the end points of the parolfactory cingulum bundle rather than the parahippocampal cingulum, suggesting that the limbic HAP-wave may travel through fornix, mammillary bodies, and the anterior nucleus of the thalamus (ANT). This was further confirmed by stimulating the ANT, which evoked the same limbic HAP-wave but with an earlier latency. Limbic subsystems have unique stimulation-evoked signatures that may be used in the future to help network pathology diagnosis.SIGNIFICANCE STATEMENT The limbic system is often compromised in diverse clinical conditions, such as epilepsy or Alzheimer's disease, and characterizing its typical circuit responses may provide diagnostic insight. Stimulation-evoked waveforms have been used in the motor system to diagnose circuit pathology. We translate this framework to limbic subsystems using human intracranial stereo EEG (sEEG) recordings that measure deeper brain areas. Our sEEG recordings describe a stimulation-evoked waveform characteristic to the memory and spatial subsystem of the limbic network that we term the "limbic HAP-wave." The limbic HAP-wave follows anatomic white matter pathways from hippocampus to thalamus to the posterior cingulum and shows promise as a distinct biomarker of signaling in the human brain memory and spatial limbic network.