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The study was designed to analyze the nNOS positive neurons present in the indusium griseum by describing their distribution and morphology. To this purpose, sagittal serial sections from paraffin or frozen autopsy specimens of corpus callosum including the overlying indusium griseum were processed by immunohistochemistry and immunofluorescence, using an antibody against the neuronal form of the enzyme nitric oxyde synthase. To test the specificity of the antibody used, Western Blot was performed in the indusium griseum of the same specimens. The stainings revealed the presence of many neuronal nitric oxyde synthase-immunopositive neurons in human indusium griseum, located along both rostral-caudal and medio-lateral directions. In particular, they were more numerous 1 mm apart from the midline, and their number peaked over the body of the corpus callosum. They showed different morphologies; in some cases, they were located at the boundary between indusium griseum and corpus callosum, more densely packed in proximity to the pial arteries penetrating into the corpus callosum. The significant presence and distribution of neuronal nitric oxyde synthase-immunopositive neurons suggests that indusium griseum likely plays a functional role in the neurovascular regulation within the corpus callosum. Graphical abstract Schematic representation of human adult IG and the neurovascular unit originating from sopracallosal artery (Sca) that branches into smaller arterioles (Br) (created in PowerPoint). The arterioles cross the three layers of IG (layers I, II and III) and penetrate into the CC separated from IG by the Virchow-Robin space (VRs). As the arterioles go deeper, this space disappears and the vascular basement membrane comes into direct contact with the astrocytic end-feets (intracallosal arterioles and capillaries). nNOS-immunopositive neurons (nNOSIP N) surround the arterioles and control the vasomotore tone secreting nitric oxyde (NO). Two morphological types of nNOSIP N can be appreciated by the use of different colors: fusiform (blue) and ovoidal (pink). Also NeuN-immunopositive neurons (N) and many astrocytes (As) are present, more numerous in IG than in CC.

The human dorsolateral prefrontal cortex (DLPFC; approximately corresponding to Brodmann areas 9 and 46) has demonstrable roles in diverse executive functions such as working memory, cognitive flexibility, planning, inhibition, and abstract reasoning. However, it remains unclear whether this is the result of one functionally homogeneous region or whether there are functional subdivisions within the DLPFC. Here, we divided the DLPFC into seven areas along rostral-caudal and dorsal-ventral axes anatomically and explored their respective patterns of structural and functional connectivity. In vivo probabilistic tractography (11 females and 13 males) and resting-state functional magnetic resonance imaging (fMRI; 57 females and 21 males) were employed to map out the patterns of connectivity from each DLPFC subregion. Structural connectivity demonstrated graded intraregional connectivity within the DLPFC. The patterns of structural connectivity between the DLPFC subregions and other cortical areas revealed that the dorsal-rostral subregions connections were restricted to other frontal and limbic areas, whereas the ventral-caudal region was widely connected to frontal, parietal, and limbic cortex. Functional connectivity analyses demonstrated that subregions of DLPFC were strongly interconnected to each other. The dorsal subregions were associated with the default mode network (DMN), while middle dorsal-rostral subregions were linked with the multiple demand network (MDN). The ventral-caudal subregion showed increased functional coupling with both DMN and MDN. Our results suggest that the connectivity of the DLPFC may be subdivided along a dorsorostral-ventrocaudal axis with differing (albeit graded) patterns of connectivity reflecting the integrative executive function of the DLPFC.SIGNIFICANCE STATEMENTResearch has shown that the dorsolateral prefrontal cortex (DLPFC) plays a role in various executive functions. By dividing the DLPFC into seven areas along rostral-caudal and dorsal-ventral axes anatomically, we explored their patterns of structural and functional connectivity. The patterns of connectivity within DLPFC subregions demonstrated graded intraregional connectivity. There were distinctive patterns of connectivity with other cortical areas in dorsal-rostral and ventral-caudal DLPFC subregions. Divisions across DLPFC subregions seem to align with their structural and functional connectivity. Our results suggest that DLPFC may be subdivided by the diagonal axis of the dorsal-ventral axis and rostral-caudal axis, supporting the framework of a functional organization along the anterior-posterior axis in the lateral PFC.

Aims To identify the metabolic pattern and prognostic predictors in anti‐gamma‐aminobutyric‐acid B (GABAB) receptor encephalitis using 18F‐fluorodeoxy‐glucose positron emission tomography (18F‐FDG‐PET). Methods Twenty‐one patients diagnosed anti‐GABAB receptor encephalitis who underwent 18F‐FDG‐PET at first hospitalization were retrospectively reviewed. 18F‐FDG‐PET images were analyzed in comparison with controls. Further group comparisons of 18F‐FDG‐PET data were carried out between prognostic subgroups. Results 18F‐FDG‐PET was abnormal in 81% patients with anti‐GABAB receptor encephalitis and was more sensitive than MRI (81% vs. 42.9%, p = 0.025). Alter limbic lobe glucose metabolism (mostly hypermetabolism) was observed in 14 patients (66.7%), of whom 10 (10/14, 71.4%) demonstrated hypermetabolism in the medial temporal lobe (MTL). Group analysis also confirmed MTL hypermetabolism in association with relative frontal and parietal hypometabolism was a general metabolic pattern. After a median follow‐up of 33 months, the group comparisons revealed that patients with poor outcome demonstrated increased metabolism in the MTL compared to those with good outcome. Conclusion 18F‐FDG‐PET may be more sensitive than MRI in the early diagnosis of anti‐GABAB receptor encephalitis. MTL hypermetabolism was associated with relative frontal or parietal hypometabolism and may serve as a prognostic biomarker in anti‐GABAB receptor encephalitis., First, we revealed pronounced MTL hypermetabolism detected by semi‐quantitative brain 18F‐FDG‐PET in patients with anti‐GABAB receptor encephalitis compared to controls, and 18F‐FDG‐PET should be considered when patients with normal MRI in suspected anti‐GABAB receptor encephalitis; second, MTL hypermetabolism may be a sensitive diagnostic and prognostic biomarker for anti‐GABAB receptor encephalitis.

Background Initial observations with the human electroencephalogram (EEG) have interpreted slow oscillations (SOs) of the EEG during deep sleep (N3) as reflecting widespread surface-negative traveling waves that originate in frontal regions and propagate across the neocortex. However, mapping SOs with a high-density array shows the simultaneous appearance of posterior positive voltage fields in the EEG at the time of the frontal-negative fields, with the typical inversion point (apparent source) around the temporal lobe. Methods Overnight 256-channel EEG recordings were gathered from 10 healthy young adults. Individual head conductivity models were created using each participant's own structural MRI. Source localization of SOs during N3 was then performed. Results Electrical source localization models confirmed that these large waves were created by focal discharges within the ventral limbic cortex, including medial temporal and caudal orbitofrontal cortex. Conclusions Although the functional neurophysiology of deep sleep involves interactions between limbic and neocortical networks, the large EEG deflections of deep sleep are not created by distributed traveling waves in lateral neocortex but instead by relatively focal limbic discharges.

Background Researchers have proposed that impaired sleep may be a causal link in the progression from Mild Cognitive Impairment (MCI) to Alzheimer's Disease (AD). Several recent findings suggest that enhancing deep sleep (N3) may improve neurological health in persons with MCI, and buffer the risk for AD. Specifically, Transcranial Electrical Stimulation (TES) of frontal brain areas, the inferred source of the Slow Oscillations (SOs) of N3 sleep, can extend N3 sleep duration and improve declarative memory for recently learned information. Recent work in our laboratory using dense array Electroencephalography (dEEG) localized the sources of SOs to anterior limbic sites – suggesting that targeting these sites with TES may be more effective for enhancing N3. Methods For the present study, we recruited 13 healthy adults (M = 42 years) to participate in three all-night sleep EEG recordings where they received low level (0.5 mA) TES designed to target anterior limbic areas and a sham stimulation (placebo). We used a convolutional neural network, trained and tested on professionally scored EEG sleep staging, to predict sleep stages for each recording. Results When compared to the sham session, limbic-targeted TES significantly increased the duration of N3 sleep. TES also significantly increased spectral power in the 0.5–1 Hz frequency band (relative to pre-TES epochs) in left temporoparietal and left occipital scalp regions compared to sham. Conclusion These results suggest that even low-level TES, when specifically targeting anterior limbic sites, can increase deep (N3) sleep and thereby contribute to healthy sleep quality.

The effect of decimetric microwaves (DMW) on the activity of pyruvate kinase (PK), one of the energy supply enzymes, was investigated in the brain structures of 3-, 6-, and 24-month-old white outbred male rats. Experimental rats were exposed on a daily basis to 10 and 30 µW/cm2 of DMW radiation for 20 min over a period of 10 days. It was established that PK activity in the cortical and subcortical brain structures, which differ in their oxygen supply, morphofunctional and phylogenetic characteristics, reacts differently to the effect of DMW: at 10 µW/cm2 it increases while at 30 µW/cm2 it decreases. In mitochondrial subcellular fractions of the brain structures, PK activity was lower at 10 µW/cm2 than at 30 µW/cm2. In cytosolic subcellular fractions, no significant differences were revealed in PK activity at different intensities of DMW radiation, while these indicators, taken separately, were significantly different compared to the control (p < 0.01; p < 0.001). There are two alternative assumptions to explain the obtained results. An increased PK activity in the brain structures studied may reflect a metabolic adaptation aimed at protecting the structural integrity and functional components of nerve cells from detrimental effects of DMW radiation. Conversely, energy deficiency due to a decline in PK activity, in turn, causes various negative secondary metabolic changes and a free-radical oxidation in nerve cells. Our data reveal that both at 10 and 30 µW/cm2 of DMW radiation the endogenous signals in the rat brain spread from cortical to subcortical structures, but PK activity does not recover to the level of the control values. It is hypothesized that under the effect of DMW radiation, the cerebellum, orbital and sensorimotor cortices serve as donors while the limbic cortex and hypothalamus as acceptors in the system of signal transduction.

The effect of decimetric microwaves (DMW) on the activity of pyruvate kinase (PK), one of the energy supply enzymes, was investigated in the brain structures of 3-, 6-, and 24-month-old white non-linear rats. Experimental rats were exposed on a daily basis for 20 min to 10 and 30 μW/cm² of DMW irradiation over a period of 10 days. It was established that PK activity in the cortical and subcortical brain structures, which differ in their oxygen supply, morphofunctional and phylogenetic characteristics, reacts differently to the effect of DMW: at 10 μW/cm² it increases while at 30 μW/cm² it decreases. In mitochondrial subcellular fractions of the brain structures, PK activity was lower at 10 μW/cm² than at 30 μW/cm². In cytosolic subcellular fractions, no significant differences were revealed in PK activity at different intensities of DMW irradiation, while these indicators, taken separately, were significantly different compared to the control (p < 0.01; p < 0.001). There are two alternative assumptions to account for the obtained results. The increased PK activity in the brain structures studied may reflect a metabolic adaptation aimed at protecting the structural integrity and functional components of nerve cells from detrimental effects of DMW irradiation. Conversely, a lack of energy due to a drop in PK activity, in turn, causes various negative secondary metabolic changes and free-radical oxidation in nerve cells. Our data indicate that both at 10 and 30 μW/cm² of DMW irradiation, endogenous signals in the rat brain are directed from cortical to subcortical structures, but PK activity does not recover to the control values. It is hypothesized that under the effect of DMW, the cerebellum, orbital and sensorimotor cortices serve as donors, while the limbic cortex and hypothalamus are acceptors in the system of signal transduction.

Lesioning or inactivating the infralimbic (IL) subregion of the medial prefrontal cortex before acquisition produces more generalized and extinction-resistant fear memories. However, whether and how it modulates memory specificity and extinction susceptibility while consolidation takes place is still unknown. The present study aims to investigate these questions using muscimol-induced temporary inactivation and anisomycin-induced protein synthesis inhibition in the rat IL following contextual fear conditioning. Results indicate that the IL activity immediately after acquisition, but not six hours later, controls memory generalization over a week, regardless of its strength. Such IL function depends on the context-shock pairing since muscimol induced no changes in animals exposed to immediate shocks or the conditioning context only. Animals in which the IL was inactivated during consolidation extinguished similarly to controls within the session but were unable to recall the extinction memory the following day. Noteworthy, these post-acquisition IL inactivation-induced effects were not associated with changes in anxiety, as assessed in the elevated plus-maze test. Anisomycin results indicate that the IL protein synthesis during consolidation contributes more to producing extinction-sensitive fear memories than memory specificity. Collectively, present results provide evidence for the IL's role in controlling generalization and susceptibility to extinction during fear memory consolidation.

Background White matter energy supply to oligodendrocytes and the axonal compartment is crucial for normal axonal function. Although gray matter glucose hypometabolism is extensively reported in Alzheimer's disease (AD), glucose and ketones, the brain's two main fuels, are rarely quantified in white matter in AD. Objective Using a dual-tracer PET method combined with a fascicle-specific diffusion MRI approach, robust to white matter hyper intensities and crossing fibers, we aimed to quantify both glucose and ketone metabolism in specific white matter fascicles associated with mild cognitive impairment (MCI; n = 51) and AD (n = 13) compared to cognitively healthy age-matched controls (Controls; n = 14). Methods Eight white matter fascicles of the limbic lobe and corpus callosum were extracted and analyzed into fascicle profiles of five sections. Glucose (18F-fluorodeoxyglucose) and ketone (11C-acetoacetate) uptake rates, corrected for partial volume effect, were calculated along each fascicle. Results The only fascicle with significantly lower glucose uptake in AD compared to Controls was the left posterior cingulate segment of the cingulum (-22%; p = 0.016). Non-significantly lower glucose uptake in this fascicle was also observed in MCI. In contrast to glucose, ketone uptake was either unchanged or higher in sections of the fornix and parahippocampal segment of the cingulum in AD. Conclusion To our knowledge, this is the first report of brain fuel uptake calculated along white matter fascicles in humans. Energetic deterioration in white matter in AD appears to be specific to glucose and occurs first in the posterior cingulum.

Background and aimsThe working memory (WM) ability of internet addicts and the topology underlying the WM processing in internet addiction (IA) are poorly understood. In this study, we employed a graph theoretical framework to characterize the topological properties of the IA brain network in the source cortical space during WM task.MethodsA sample of 24 subjects with IA and 23 matched healthy controls (HCs) performed visual 2-back task. Exact Low Resolution Electromagnetic Tomography was adopted to project the pre-processed EEG signals into source space. Subsequently, Lagged phase synchronization was calculated between all pairs of Brodmann areas, the graph theoretical approaches were then employed to estimate the brain topological properties of all participants during the WM task.ResultsWe found better WM behavioral performance in IA subjects compared with the HCs. Moreover, compared to the HC group, more integrated and hierarchical brain network was revealed in the IA subjects in alpha band. And altered regional centrality was mainly resided in frontal and limbic lobes. In addition, significant relationships between the IA severity and the significant altered graph indices were found.ConclusionsIn conclusion, these findings provide evidence to support the notion that altered topological configuration may underline changed WM function observed in IA.

Different dimensions of adversity may affect mental health through distinct neurobiological mechanisms, though current supporting evidence consists largely of cross-sectional associations between threat or deprivation and fronto-limbic circuitry. In this exploratory three-wave longitudinal study spanning ages 9–19 years, we examined the associations between experiences of unpredictability, threat, and deprivation with the development of functional connectivity within and between three brain networks implicated in psychopathology: the salience (SAL), default mode (DMN), and fronto-parietal (FPN) networks, and tested whether network trajectories moderated associations between adversity and changes in internalizing symptoms. Connectivity decreased with age on average; these changes differed by dimension of adversity. Whereas family-level deprivation was associated with lower initial levels and more stability across most networks, unpredictability was associated with stability only in SAL connectivity, and threat was associated with stability in FPN and DMN-SAL connectivity. In youth exposed to higher levels of any adversity, lower initial levels and more stability in connectivity were related to smaller increases in internalizing symptoms. Our findings suggest that whereas deprivation is associated with widespread neurodevelopmental differences in cognitive and emotion processing networks, unpredictability is related selectively to salience detection circuitry. Studies with wider developmental windows should examine whether these neurodevelopmental alterations are adaptive or serve to maintain internalizing symptoms.

Von Economo neurons (VENs) have been mentioned in the medical literature since the second half of the 19th century; however, it was not until the second decade of the 20th century that their cytomorphology was described in detail. To date, VENs have been found in limbic sectors of the frontal, temporal and insular lobes. In humans, their density seems to decrease in the caudo-rostral and ventro-dorsal direction; that is, from the anterior regions of the cingulate and insular cortices towards the frontal pole and the superior frontal gyrus. Several studies have provided similar descriptions of the shape of the VEN soma, but the size of the soma varies from one cortical region to another. There is consensus among different authors about the selective vulnerability of VENs in certain pathologies, in which a deterioration of the capacities involved in social behaviour is observed. In this review, we propose that the restriction of VENs towards the sectors linked to limbic information processing in Homo sapiens gives them a possible functional role in relation to the structures in which they are located. However, given the divergence in characteristics such as location, density, size and biochemical profile among VENs of different cortical sectors, the activities in which they participate could allow them to partake in a wide spectrum of neurological functions, including autonomic responses and executive functions.

The neural mechanisms involved in the processing of vocalizations and music were compared, in order to observe possible similarities in the encoding of their emotional content. Positive and negative emotional vocalizations (e.g. laughing, crying) and violin musical stimuli digitally extracted from them were used as stimuli. They shared the melodic profile and main pitch/frequency characteristics. Participants listened to vocalizations or music while detecting rare auditory targets (bird tweeting, or piano's arpeggios). EEG was recorded from 128 sites. P2, N400 and Late positivity responses of ERPs were analysed. P2 peak was earlier in response to vocalizations, while P2 amplitude was larger to positive than negative stimuli. N400 was greater to negative than positive stimuli. LP was greater to vocalizations than music and to positive than negative stimuli. Source modelling using swLORETA suggested that, among N400 generators, the left middle temporal gyrus and the right uncus responded to both music and vocalizations, and more to negative than positive stimuli. The right parahippocampal region of the limbic lobe and the right cingulate cortex were active during music listening, while the left superior temporal cortex only responded to human vocalizations. Negative stimuli always activated the right middle temporal gyrus, whereas positively valenced stimuli always activated the inferior frontal cortex. The processing of emotional vocalizations and music seemed to involve common neural mechanisms. Notation obtained from acoustic signals showed how emotionally negative stimuli tended to be in Minor key, and positive stimuli in Major key, thus shedding some lights on the brain ability to understand music.

International audience; The subthalamic nucleus (STN) receives direct cortical inputs which constitute the so-called hyperdirect pathway. In monkeys, motor cortices innervate the whole extent of the STN whereas limbic cortices innervate only its anteromedial part extending more medially outside the nucleus. Tractography studies in humans have also identified motor cortical inputs to the STN, but little is known about the associative and limbic cortical projections. Therefore, the aim of this study was to investigate the anatomo-functional organization of the cortical projections to the STN and to the adjacent medial subthamic region (MSR). We used diffusion-weighted imaging-based tractography acquired from 30 subjects from the Human Connectome Project. We performed a whole-brain probabilistic tractography using MRTrix and extracted streamlines of interest between 39 cortical masks and both the STN and the MSR to provide track-density maps. Agglomerative clustering method was used to classify the voxels of the regions of interest. We found that the STN receives major inputs from the sensorimotor cortices and few inputs from the limbic cortices. On the other hand, the MSR receives mainly cortical limbic projections and few from the sensorimotor cortices. Weak connections were found between the associative cortices and both the STN and the MSR. We found a dominant motor cluster located in the posterolateral STN, a limbic cluster located medially in the MSR, and an intermediate motor-limbic cluster in between. Our findings show that the hyperdirect pathway is anatomo-functionally organized with a poor participation of associative cortices.

The prelimbic and infralimbic cortices of the rodent medial prefrontal cortex mediate the effects of context and goals on instrumental behavior. Recent work from our laboratory has expanded this understanding. Results have shown that the prelimbic cortex is important for the modulation of instrumental behavior by the context in which the behavior is learned (but not other contexts), with context potentially being broadly defined (to include at least previous behaviors). We have also shown that the infralimbic cortex is important in the expression of extensively-trained instrumental behavior, regardless of whether that behavior is expressed as a stimulus-response habit or a goal-directed action. Some of the most recent data suggest that infralimbic cortex may control the currently active behavioral state (e.g., habit vs. action or acquisition vs. extinction) when two states have been learned. We have also begun to examine prelimbic and infralimbic cortex function as key nodes of discrete circuits and have shown that prelimbic cortex projections to an anterior region of the dorsomedial striatum are important for expression of minimally-trained instrumental behavior. Overall, the use of an associative learning perspective on instrumental learning has allowed the research to provide new perspectives on how these two “cognitive” brain regions contribute to instrumental behavior.

Background: Changes in the amplitude of low-frequency fluctuations (ALFF) and the fractional amplitude of low-frequency fluctuations (fALFF) have provided stronger evidence for the pathophysiology of cognitive impairment. Whether the altered patterns of ALFF and fALFF differ in amnestic cognitive impairment (aMCI) and vascular mild cognitive impairment (vMCI) is largely unknown. The purpose of this study was to explore the ALFF/fALFF changes in the two diseases and to further explore whether they contribute to the diagnosis and differentiation of these diseases.Methods: We searched PubMed, Ovid, and Web of Science databases for articles on studies using the ALFF/fALFF method in patients with aMCI and vMCI. Based on the activation likelihood estimation (ALE) method, connectivity modeling based on coordinate meta-analysis and functional meta-analysis was carried out.Results: Compared with healthy controls (HCs), patients with aMCI showed increased ALFF/fALFF in the bilateral parahippocampal gyrus/hippocampus (PHG/HG), right amygdala, right cerebellum anterior lobe (CAL), left middle temporal gyrus (MTG), left cerebrum temporal lobe sub-gyral, left inferior temporal gyrus (ITG), and left cerebrum limbic lobe uncus. Meanwhile, decreased ALFF/fALFF values were also revealed in the bilateral precuneus (PCUN), bilateral cuneus (CUN), and bilateral posterior cingulate (PC) in patients with aMCI. Compared with HCs, patients with vMCI predominantly showed decreased ALFF/fALFF in the bilateral CUN, left PCUN, left PC, and right cingulate gyrus (CG).Conclusions: The present findings suggest that ALFF and fALFF displayed remarkable altered patterns between aMCI and vMCI when compared with HCs. Thus, the findings of this study may serve as a reliable tool for distinguishing aMCI from vMCI, which may help understand the pathophysiological mechanisms of these diseases.

Migraine is a chronic neurological disorder characterized by attacks of moderate or severe headache accompanying functionally and structurally maladaptive changes in brain. As the headache days/month is often measured by patient self‐report and tends to be overestimated than actually experienced, the possibility of using neuroimaging data to predict migraine attack frequency is of great interest. To identify neuroimaging features that could objectively evaluate patients' headache days, a total of 179 migraineurs were recruited from two data center with one dataset used as the training/test cohort and the other used as the validating cohort. The guidelines for controlled trials of prophylactic treatment of chronic migraine in adults were used to identify the frequency of attacks and migraineurs were divided into low (MOl) and high (MOh) subgroups. Whole‐brain functional connectivity was used to build multivariate logistic regression models with model iteration optimization to identify MOl and MOh. The best model accurately discriminated MOh from MOl with AUC of 0.91 (95%CI [0.86, 0.95]) in the training/test cohort and 0.79 in the validating cohort. The discriminative features were mainly located within the limbic lobe, frontal lobe, and temporal lobe. Permutation tests analysis demonstrated that the classification performance of these features was significantly better than chance. Furthermore, the indicator of functional connectivity had a higher odds ratio than behavioral variables with implementing a holistic regression analysis. The current findings suggested that the migraine attack frequency could be distinguished by using machine‐learning algorithms, and highlighted the role of brain functional connectivity in revealing underlying migraine‐related neurobiology.

Objective:Bilateral anterior capsulotomy (BAC) is one of the ablative neurosurgical procedures used to treat major depressive disorder or obsessive-compulsive disorder when all other therapies fail. Tristolysis, a reduction in sadness, is the most striking clinical effect of BAC and is seen in the first 1 to 2 weeks after surgery. This retrospective study measured regional cerebral blood flow (rCBF) following surgery to identify which cortical regions were impacted and could account for this clinical effect.Methods:All patients had their capsulotomies done in Vancouver by the same team. Pre- and postoperative single-photon emission computed tomography perfusion scans were analyzed for 10 patients with major depressive disorder and 3 with obsessive-compulsive disorder. rCBF was measured semiquantitatively by calculating the ratio between an identified region of interest and a whole brain reference area.Results:Decreased rCBF was found in the paraterminal gyri. Increased rCBF was found in the dorsolateral prefrontal cortices and in the left lateral temporal lobe.Conclusions:BAC causes hypoactivity in the paraterminal gyri and is the most likely explanation for its tristolytic effect, suggesting that the paraterminal gyrus is the limbic cortical locus for the emotion of sadness. Increased activity in the dorsolateral prefrontal cortices may be occurring via connectional diaschisis, and suppression by overactive paraterminal gyri during depression may account for some of the neurocognitive deficits observed during depressive episodes.

BACKGROUND: Clinical levels of social anxiety disorder (SAD) often appear during childhood and rise to a peak during late adolescence. The temperament trait behavioral inhibition (BI), evident early in childhood, has been linked to increased risk for SAD. Functional and structural variation in brain regions associated with the identification of, and response to, fear may support the BI-SAD relation. While relevant functional studies are emerging, the few extant structural studies have focused on adult samples with mixed findings. METHODS: A moderated-mediation model was used to examine the relations between BI, SAD symptoms, and brain-volume individual differences in a sample of children at risk for anxiety (ages 9–12; N=130, 52 BI). RESULTS: Our findings indicate that at higher levels of BI, children with smaller anterior insula volumes showed stronger correlations between BI and SAD. In addition, larger ventrolateral prefrontal cortex (vlPFC) volumes were associated with fewer SAD symptoms. CONCLUSIONS: These findings support previous reports linking SAD levels with variations in volume and reactivity in both limbic (insula) and prefrontal (vlPFC) regions. These findings set the foundation for further examination of networks of neural structures that influence the transition from BI to SAD across development, helping further clarify mechanisms of risk and resilience. The data that support the findings of this study are openly available in clinical trial registration information— http://clinicaltrials.gov/; Attention and Social Behavior in Children (BRAINS); .