GABA in the anterior cingulate cortex mediates the association of white matter hyperintensities with executive function: a magnetic resonance spectroscopy study.

White matter hyperintensities (WMH) and gamma-aminobutyric acid (GABA) are associated with executive function. Multiple studies suggested cortical alterations mediate WMH-related cognitive decline. The aim of this study was to investigate the crucial role of cortical GABA in the WMH patients. In the 87 WMH patients (46 mild and 41 moderate to severe) examined in this study, GABA levels in the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC) assessed by the Meshcher-Garwood point resolved spectroscopy (MEGA-PRESS) sequence, WMH volume and executive function were compared between the two groups. Partial correlation and mediation analyses were carried out to examine the GABA levels in mediating the association between WMH volume and executive function. Patients with moderate to severe WMH had lower GABA+/Cr in the ACC (p = 0.034) and worse executive function (p = 0.004) than mild WMH patients. In all WMH cases, the GABA+/Cr levels in the ACC mediated the negative correlation between WMH and executive function (ab: effect = -0.020, BootSE = 0.010, 95% CI: -0.042 to -0.004). This finding suggested GABA+/Cr levels in the ACC might serve as a protective factor or potential target for preventing the occurrence and progression of executive function decline in WMH people.

The neural correlates of topographical disorientation-a lesion analysis study.

Topographical disorientation refers to the selective inability to orient oneself in familiar surroundings. However, to date its neural correlates remain poorly understood. Here we use quantitative lesion analysis and a lesion network mapping approach in order to investigate seven patients with topographical disorientation. Our findings link not only the posterior parahippocampal gyrus (PHG) and retrosplenial cortex but also the lingual gyrus, the precuneus and the fusiform gyrus to topographical disorientation. We propose that topographical disorientation is due to the inability to integrate familiar landmarks within a framework of allocentric and egocentric orientation, supported by a neural network including the posterior PHG, the retrosplenial and the lingual cortex.

Functional Connectivity Alterations and Molecular Characterization of the Anterior Cingulate Cortex in Tinnitus Pathology without Hearing Loss.

Compared with individuals with hearing loss, tinnitus patients without hearing loss have more psychological or emotional problems. Tinnitus is closely associated to abnormal metabolism and function of the limbic system, a key brain region for emotion experience, but the underlying molecular mechanism remains unknown. Using whole-brain microvasculature dynamics imaging, the anterior cingulate cortex (ACC) is identified as a key brain region of limbic system involve in the onset of salicylate-induced tinnitus in mice. In the tinnitus group, there is enhanced purine metabolism, oxidative phosphorylation, and a distinct pattern of phosphorylation in glutamatergic synaptic pathway according to the metabolome profiles, quantitative proteomic, and phosphoproteomic data of mice ACC tissue. Electroencephalogram in tinnitus patients with normal hearing thresholds show that the functional connectivity between pregenual anterior cingulate cortex and the primary auditory cortex is significantly increased for high-gamma frequency band, which is positively correlated with the serum glutamate level. These findings indicate that ACC plays an important role in the pathophysiology of tinnitus by interacting with the primary auditory cortex and provide potential molecular targets in the ACC for tinnitus treatment.

Childhood trauma and cortical thickness in healthy women, women with post-traumatic stress disorder, and women with borderline personality disorder.

BACKGROUND: Structural brain changes have been associated with childhood trauma (CT) and several trauma-associated mental disorders. It is not known whether specific brain alterations are rather associated with CT as such or with disorders that are common sequelae of CT. In this study, we characterized cortical thickness in three distinct groups with CT: healthy women (HC/CT), women with posttraumatic stress disorder (PTSD/CT) and women with borderline personality disorder (BPD/CT). These three CT-exposed groups were compared with healthy controls not exposed to CT (HC). METHODS: We recruited 129 women (n = 70 HC, n = 25 HC/CT, n = 14 PTSD/CT, and n = 20 BPD/CT) and acquired T1-weighted anatomical images. FreeSurfer was used for conducting whole-brain cortical thickness between-group comparisons, applying separate generalized linear models to compare cortical thickness of each CT-exposed group with HC. RESULTS: The HC/CT group had lower cortical thickness in occipital lobe areas (right lingual gyrus, left lateral occipital lobe) than the HC group. The BPD/CT group showed a broader pattern of reduced cortical thickness compared to the HC group, including the bilateral superior frontal gyrus, and bilateral isthmus, the right posterior, and left caudal anterior of the cingulate cortex as well as the right lingual gyrus of the occipital lobe. We found no differences between PTSD/CT and HC. CONCLUSIONS: Cortical thickness reduction in the right lingual gyrus of the occipital lobe seem to be related to CT but is also present in BPD patients even after adjusting for severity of CT. Possibly, reduced cortical thickness in the lingual gyrus presents a CT-related vulnerability factor for CT-related adult psychopathologies such as BPD. Reduced cortical thickness in the frontal and cingulate cortex may represent unique neuroanatomical markers of BPD possibly related to difficulties in emotion regulation.

Measuring Brain Temperature in Youth Bipolar Disorder Using a Novel Magnetic Resonance Imaging Approach: A Proof-of-concept Study.

BACKGROUND: There is evidence of alterations in mitochondrial energy metabolism and cerebral blood flow (CBF) in adults and youth with bipolar disorder (BD). Brain thermoregulation is based on the balance of heat-producing metabolism and heat-dissipating mechanisms, including CBF. OBJECTIVE: To examine brain temperature, and its relation to CBF, in relation to BD and mood symptom severity in youth. METHODS: This study included 25 youth participants (age 17.4 ± 1.7 years; 13 BD, 12 control group (CG)). Magnetic resonance spectroscopy data were acquired to obtain brain temperature in the left anterior cingulate cortex (ACC) and the left precuneus. Regional estimates of CBF were provided by arterial spin labeling imaging. Analyses used general linear regression models, covarying for age, sex, and psychiatric medications. RESULTS: Brain temperature was significantly higher in BD compared to CG in the precuneus. A higher ratio of brain temperature to CBF was significantly associated with greater depression symptom severity in both the ACC and precuneus within BD. Analyses examining the relationship of brain temperature or CBF with depression severity score did not reveal any significant finding in the ACC or the precuneus. CONCLUSION: The current study provides preliminary evidence of increased brain temperature in youth with BD, in whom reduced thermoregulatory capacity is putatively associated with depression symptom severity. Evaluation of brain temperature and CBF in conjunction may provide valuable insight beyond what can be gleaned by either metric alone. Larger prospective studies are warranted to further evaluate brain temperature and its association with CBF concerning BD.

Structural inequities contribute to racial/ethnic differences in neurophysiological tone, but not threat reactivity, after trauma exposure.

Considerable racial/ethnic disparities persist in exposure to life stressors and socioeconomic resources that can directly affect threat neurocircuitry, particularly the amygdala, that partially mediates susceptibility to adverse posttraumatic outcomes. Limited work to date, however, has investigated potential racial/ethnic variability in amygdala reactivity or connectivity that may in turn be related to outcomes such as post-traumatic stress disorder (PTSD). Participants from the AURORA study (n = 283), a multisite longitudinal study of trauma outcomes, completed functional magnetic resonance imaging and psychophysiology within approximately two-weeks of trauma exposure. Seed-based amygdala connectivity and amygdala reactivity during passive viewing of fearful and neutral faces were assessed during fMRI. Physiological activity was assessed during Pavlovian threat conditioning. Participants also reported the severity of posttraumatic symptoms 3 and 6 months after trauma. Black individuals showed lower baseline skin conductance levels and startle compared to White individuals, but no differences were observed in physiological reactions to threat. Further, Hispanic and Black participants showed greater amygdala connectivity to regions including the dorsolateral prefrontal cortex (PFC), dorsal anterior cingulate cortex, insula, and cerebellum compared to White participants. No differences were observed in amygdala reactivity to threat. Amygdala connectivity was associated with 3-month PTSD symptoms, but the associations differed by racial/ethnic group and were partly driven by group differences in structural inequities. The present findings suggest variability in tonic neurophysiological arousal in the early aftermath of trauma between racial/ethnic groups, driven by structural inequality, impacts neural processes that mediate susceptibility to later PTSD symptoms.

Transcriptional signal and cell specificity of genes related to cortical structural differences of post-traumatic stress disorder.

Due to the diversity of traumatic events, the diagnosis of Post-traumatic Stress Disorder is heterogeneous. The pathogenesis has been explored in the fields of brain imaging and genomics separately, but the results are inconsistent. Previous research evidenced that there existed structural differences between PTSD and healthy controls in multiple brain regions. This study further looked into the differences of brain structure in PTSD at the whole brain level and analyzed the difference-related genomes. The brain structure imaging data of 36 patients and 32 healthy controls were taken as morphological indexes. Partial least squares regression and transcriptome data were used to extract genomes related to structural differences. Additional data sets were used to study transcription characteristics of genome. Morphological differences were found in cingulate gyrus between patients and control group. Differentially expressed genes related to Morphometric similarity networks difference space were also observed. The obtained genes (i.e., RORA, PRKG1 and FKBP5) were proved to be related to the disorder with no significant correlation with other mental illnesses. In the subsequent cell type analysis, astrocytes, excitatory neurons and inhibitory neurons were evidenced to have the most significant correlation with these genes. This study found morphologically different brain regions related to PTSD. The related genome transcription analysis connects the structural differences and molecular mechanisms.

A transdiagnostic network for psychiatric illness derived from atrophy and lesions.

Psychiatric disorders share neurobiology and frequently co-occur. This neurobiological and clinical overlap highlights opportunities for transdiagnostic treatments. In this study, we used coordinate and lesion network mapping to test for a shared brain network across psychiatric disorders. In our meta-analysis of 193 studies, atrophy coordinates across six psychiatric disorders mapped to a common brain network defined by positive connectivity to anterior cingulate and insula, and by negative connectivity to posterior parietal and lateral occipital cortex. This network was robust to leave-one-diagnosis-out cross-validation and specific to atrophy coordinates from psychiatric versus neurodegenerative disorders (72 studies). In 194 patients with penetrating head trauma, lesion damage to this network correlated with the number of post-lesion psychiatric diagnoses. Neurosurgical ablation targets for psychiatric illness (four targets) also aligned with the network. This convergent brain network for psychiatric illness may partially explain high rates of psychiatric comorbidity and could highlight neuromodulation targets for patients with more than one psychiatric disorder.

Impaired Non-Selective Response Inhibition in Obsessive-Compulsive Disorder.

Two prominent features of obsessive-compulsive disorder (OCD) are the inability to inhibit intrusive thoughts and behaviors and pathological doubt or intolerance of uncertainty. Previous study showed that uncertain context modeled by equiprobable presentation of excitatory (Go) and inhibitory (NoGo) stimuli requires non-selective response inhibition in healthy subjects. In other words, it requires transient global inhibition triggered not only by excitatory stimuli but also by inhibitory stimuli. Meanwhile, it is unknown whether OCD patients show abnormal brain activity of the non-selective response inhibition system. In order to test this assumption, we performed an fMRI study with an equiprobable Go/NoGo task involving fourteen patients with OCD and compared them with 34 healthy controls. Patients with OCD showed pathological slowness in the Go/NoGo task. The non-selective response inhibition system in OCD included all brain areas seen in healthy controls and, in addition, involved the right anterior cingulate cortex (ACC) and the anterior insula/frontal operculum (AIFO). Moreover, a between-group comparison revealed hypoactivation of brain regions within cingulo-opercular and cortico-striato-thalamo-cortical (CSTC) circuits in OCD. Among hypoactivated areas, the right ACC and the right dorsolateral prefrontal cortex (DLPFC) were associated with non-selective inhibition. Furthermore, regression analysis showed that OCD slowness was associated with decreased activation in cingulate regions and two brain areas related to non-selective inhibition: the right DLPFC and the right inferior parietal lobule (IPL). These results suggest that non-selective response inhibition is impaired in OCD, which could be a potential explanation for a relationship between inhibitory deficits and the other remarkable characteristic of OCD known as intolerance of uncertainty.

Childhood maltreatment is associated with cortical thinning in people with eating disorders.

Childhood maltreatment (CM) is a non-specific risk factor for eating disorders (ED) and is associated with a greater severity in their clinical presentation and poorer treatment outcome. These data suggest that maltreated people with ED may be biologically other than clinically different from non-maltreated people. The aim of the present study was to investigate cortical thickness (CT), a possible biomarker of neurodevelopment, in people with ED with or without history of CM and in healthy women. Twenty-four healthy women, 26 with anorexia nervosa and 24 with bulimia nervosa underwent a 3T MRI scan. All participants filled in the childhood trauma questionnaire. All neuroimaging data were processed by FreeSurfer. Twenty-four participants with ED were identified as maltreated and 26 participants with ED as non-maltreated. All healthy women were non-maltreated. Compared to healthy women, maltreated people with ED showed lower CT in the left rostral anterior cingulate gyrus, while compared to people with ED without history of CM showed lower CT values in the left superior frontal and in right caudal middle frontal and superior parietal gyri. No significant differences emerged in CT measures between healthy women and people with ED without history of CM. The present findings show for the first time that in adult people with ED childhood maltreatment is associated with cortical thinning in areas implicated in the modulation of brain processes that are acknowledged to play a role in the psychopathology of ED.

Cortical and subcortical grey matter correlates of psychopathic traits in a Japanese community sample of young adults: sex and configurations of factors' level matter!

While neuroimaging research has examined the structural brain correlates of psychopathy predominantly in clinical/forensic male samples from western countries, much less is known about those correlates in non-western community samples. Here, structural magnetic resonance imaging data were analyzed using voxel- and surface-based morphometry to investigate the neuroanatomical correlates of psychopathic traits in a mixed-sex sample of 97 well-functioning Japanese adults (45 males, 21-39 years; M = 27, SD = 5.3). Psychopathic traits were assessed using the Self-Report Psychopathy Scale (SRP-SF; 4th Edition). Multiple regression analysis showed greater Factor 1 scores were associated with higher gyrification in the lingual gyrus, and gray matter volume in the anterior cingulate cortex and amygdala/hippocampus border. Total psychopathy and Factor 1 scores interacted with sex to, respectively, predict cortical thickness in the precuneus and gyrification in the superior temporal gyrus. Finally, Factor 1 and Factor 2 traits interacted to predict gyrification in the posterior cingulate cortex. These preliminary data suggest that, while there may be commonalities in the loci of structural brain correlates of psychopathic traits in clinical/forensic and community samples, the nature of that association might be different (i.e. positive) and may vary according to sex and configurations of factors' level.

Cingulate sulcus morphology and paracingulate sulcus variations: Anatomical and radiological studies.

The sulci and gyri found across the cerebrum differ in morphology between individuals. The cingulate sulcus is an important landmark for deciding the surgical approach for neighboring pathological lesions. Identifying the anatomical variations of anterior cingulate cortex morphology would help to determine the safe-entry route through neighboring lesions. In this study, magnetic resonance imaging data acquired from 149 healthy volunteers were investigated retrospectively for anatomical variations of the paracingulate sulcus. Also, human cadaveric brain hemispheres were investigated for cingulate and paracingulate sulcus anatomy. All participants had cingulate sulci in both hemispheres (n = 149, 100%). Three types of paracingulate sulcus patterns were identified: "prominent," "present," and "absent." Hemispheric comparisons indicated that the paracingulate sulcus is commonly "prominent" in the left hemisphere (n = 48, 32.21%) and more commonly "absent" in the right hemisphere (n = 73, 48.99%). Ten (6.71%) people had a prominent paracingulate sulcus in both the right and left hemispheres. Seven (4.70%) of them were male, and 3 (2.01%) of them were female. Paracingulate sulci were present in both hemispheres in 19 people (12.75%), of which 9 (6.04%) were male and 10 (6.71%) were female. There were 35 (23.49%) participants without paracingulate sulci in both hemispheres. Eleven (7.38%) were male and 24 (16.11%) were female. There were 73 (48.99%) participants without right paracingulate sulcus and 57 (38.26%) participants without left paracingulate sulcus (p = 0.019). In the examinations of the cadaver hemispheres, the paracingulate sulcus was present and prominent in 25%, and the intralimbic sulcus was present in 15%. It has been observed that the paracingulate sulcus is more prominent in the normal male brain compared to females. In females, there were more participants without paracingulate sulcus. This study shows that there are both hemispheric and sex differences in the anatomy of the paracingulate sulcus. Understanding the cingulate sulcus anatomy and considering the variations in the anterior cingulate cortex morphology during surgery will help surgeons to orient this elegant and complex area.

The left-lateralisation of citrate synthase activity in the anterior cingulate cortex of male violent suicide victims.

The anterior cingulate cortex (AC) as a part of prefrontal cortex plays a crucial role in behavioural regulation, which is profoundly disturbed in suicide. Citrate synthase (CS) is a key enzyme of tricarboxylic acid cycle fundamental for brain energetics and neurotransmitter synthesis, which are deteriorated in suicidal behaviour. However, CS activity has not been yet studied in brain structures of suicide victims. CS activity assay was performed bilaterally on frozen samples of the rostral part of the AC of 24 violent suicide completers (21 males and 3 females) with unknown psychiatric diagnosis and 24 non-suicidal controls (20 males and 4 females). Compared to controls, suicide victims revealed decreased CS activity in the right AC, however, insignificant. Further statistical analysis of laterality index revealed the left-lateralisation of CS activity in the AC in male suicides compared to male controls (U-test P = 0.0003, corrected for multiple comparisons). The results were not confounded by postmortem interval, blood alcohol concentration, age, and brain weight. Our findings suggest that disturbed CS activity in the AC plays a role in suicide pathogenesis and correspond with our previous morphological and molecular studies of prefrontal regions in suicide.

Reduced cortical neuron number and neuron density in schizophrenia with focus on area 24: a post-mortem case-control study.

Structural and functional abnormalities of the anterior cingulate cortex (ACC) have frequently been identified in schizophrenia. Alterations of von Economo neurons (VENs), a class of specialized projection neurons, have been found in different neuropsychiatric disorders and are also suspected in schizophrenia. To date, however, no definitive conclusions can be drawn about quantitative histologic changes in the ACC in schizophrenia because of a lack of rigorous, design-based stereologic studies. In the present study, the volume, total neuron number and total number of VENs in layer V of area 24 were determined in both hemispheres of postmortem brains from 12 male patients with schizophrenia and 11 age-matched male controls. To distinguish global from local effects, volume and total neuron number were also determined in the whole area 24 and whole cortical gray matter (CGM). Measurements were adjusted for hemisphere, age, postmortem interval and fixation time using an ANCOVA model. Compared to controls, patients with schizophrenia showed alterations, with lower mean total neuron number in CGM (- 14.9%, P = 0.007) and in layer V of area 24 (- 21.1%, P = 0.002), and lower mean total number of VENs (- 28.3%, P = 0.027). These data provide evidence for ACC involvement in the pathophysiology of schizophrenia, and complement neuroimaging findings of impaired ACC connectivity in schizophrenia. Furthermore, these results support the hypothesis that the clinical presentation of schizophrenia, particularly deficits in social cognition, is associated with pathology of VENs.

Higher polygenic risk scores for anxiety disorders are associated with reduced area in the anterior cingulate gyrus.

Anxiety disorders are heterogeneous, show a moderate genetic contribution and are associated with inconsistent cortical structure alterations. Here, we investigated whether genetic factors for anxiety disorders contribute to cortical alterations by conducting polygenic risk score (PRS) analyses. We calculated PRSs for anxiety disorders at several P value thresholds (from PT ≤ 5.0 × 10-8 to PT ≤ 1.0) based on the latest large-scale genome-wide association study of anxiety disorders from the UK biobank (25,453 cases; 58,113 controls) in an independent sample of psychiatrically and physically healthy subjects (n = 174). Using regression after adjusting for confounding factors, we tested whether these PRSs were associated with the surface area and cortical thickness in 34 bilateral brain regions extracted using FreeSurfer. A higher PRS for anxiety disorders at PT ≤ 1.0 was significantly associated with a reduced right caudal anterior cingulate area (beta = -0.25, puncorrected = 9.51 × 10-4, pcorrected = 0.032). PRSs based on more common SNPs, especially from PT ≤ 0.01 to PT ≤ 1.0, were associated with the right caudal anterior cingulate area (a maximum at PT ≤ 0.5: R2 = 0.066, beta = -0.27, puncorr = 3.81 × 10-4, pcorr = 0.013). Furthermore, individuals in the highest quartile for anxiety disorder PRS had lower surface area and volume in the right anterior cingulate gyrus than those in the lowest quartile. We suggest a shared genetic etiology between anxiety disorders and structural features of the anterior cingulate gyrus, possibly contributing to the pathogenesis of anxiety disorders via emotional dysregulations. Our findings suggest the potential usefulness of PRS to reduce pathological heterogeneity among anxiety disorders.

Elevated Monoamine Oxidase-A in Anterior Cingulate of Post-Mortem Human Parkinson's Disease: A Potential Surrogate Biomarker for Lewy Bodies?

Lewy bodies (LB) play a neuropathological role in Parkinson's disease (PD). Our goal was to evaluate LB using anti-ubiquitin immunohistochemistry (UIHC) and find correlations with monoamine oxidase-A (MAO-A) using imaging agent, [18F]FAZIN3. Human post-mortem anterior cingulate (AC) and corpus callosum (CC) from control subjects (CN), n = 6; age 81-90 LB = 0 and PD, n = 6, age 77-89, LB = III-IV were sectioned (10 µm slices). Brain slices were immunostained with anti-ubiquitin for LB (UIHC) and analyzed using QuPath for percent anti-ubiquitin per unit area (µm2). Adjacent brain slices were incubated with [18F]FAZIN3 and cortical layers I-III, IV-VI and CC (white matter) regions were quantified for the binding of [18F]FAZIN3. UIHC was correlated with [18F]FAZIN3 binding. All PD brains were positively UIHC stained and confirmed presence of LB. Outer cortical layers (I-III) of PD AC had 21% UIHC while inner layers (IV-VI) had >75% UIHC. In the CN brains LB were absent (<1% UIHC). Increased [18F]FAZIN3 binding to MAO-A in AC was observed in all PD subjects. [18F]FAZIN3 ratio in PD was AC/CC = 3.57 while in CN subjects it was AC/CC = 2.24. Increases in UIHC µm2 correlated with [18F]FAZIN3 binding to MAO-A in DLU/mm2. Increased [18F]FAZIN3 binding to MAO-A in PD is a potential novel "hot spot" PET imaging approach.

The Intranigral Infusion of Human-Alpha Synuclein Oligomers Induces a Cognitive Impairment in Rats Associated with Changes in Neuronal Firing and Neuroinflammation in the Anterior Cingulate Cortex.

Parkinson's disease (PD) is a complex pathology causing a plethora of non-motor symptoms besides classical motor impairments, including cognitive disturbances. Recent studies in the PD human brain have reported microgliosis in limbic and neocortical structures, suggesting a role for neuroinflammation in the development of cognitive decline. Yet, the mechanism underlying the cognitive pathology is under investigated, mainly for the lack of a valid preclinical neuropathological model reproducing the disease's motor and non-motor aspects. Here, we show that the bilateral intracerebral infusion of pre-formed human alpha synuclein oligomers (H-αSynOs) within the substantia nigra pars compacta (SNpc) offers a valid model for studying the cognitive symptoms of PD, which adds to the classical motor aspects previously described in the same model. Indeed, H-αSynOs-infused rats displayed memory deficits in the two-trial recognition task in a Y maze and the novel object recognition (NOR) test performed three months after the oligomer infusion. In the anterior cingulate cortex (ACC) of H-αSynOs-infused rats the in vivo electrophysiological activity was altered and the expression of the neuron-specific immediate early gene (IEG) Npas4 (Neuronal PAS domain protein 4) and the AMPA receptor subunit GluR1 were decreased. The histological analysis of the brain of cognitively impaired rats showed a neuroinflammatory response in cognition-related regions such as the ACC and discrete subareas of the hippocampus, in the absence of any evident neuronal loss, supporting a role of neuroinflammation in cognitive decline. We found an increased GFAP reactivity and the acquisition of a proinflammatory phenotype by microglia, as indicated by the increased levels of microglial Tumor Necrosis Factor alpha (TNF-α) as compared to vehicle-infused rats. Moreover, diffused deposits of phospho-alpha synuclein (p-αSyn) and Lewy neurite-like aggregates were found in the SNpc and striatum, suggesting the spreading of toxic protein within anatomically interconnected areas. Altogether, we present a neuropathological rat model of PD that is relevant for the study of cognitive dysfunction featuring the disease. The intranigral infusion of toxic oligomeric species of alpha-synuclein (α-Syn) induced spreading and neuroinflammation in distant cognition-relevant regions, which may drive the altered neuronal activity underlying cognitive deficits.

Shank2/3 double knockout-based screening of cortical subregions links the retrosplenial area to the loss of social memory in autism spectrum disorders.

Members of the Shank protein family are master scaffolds of the postsynaptic architecture and mutations within the SHANK genes are causally associated with autism spectrum disorders (ASDs). We generated a Shank2-Shank3 double knockout mouse that is showing severe autism related core symptoms, as well as a broad spectrum of comorbidities. We exploited this animal model to identify cortical brain areas linked to specific autistic traits by locally deleting Shank2 and Shank3 simultaneously. Our screening of 10 cortical subregions revealed that a Shank2/3 deletion within the retrosplenial area severely impairs social memory, a core symptom of ASD. Notably, DREADD-mediated neuronal activation could rescue the social impairment triggered by Shank2/3 depletion. Data indicate that the retrosplenial area has to be added to the list of defined brain regions that contribute to the spectrum of behavioural alterations seen in ASDs.

Regional metabolic heterogeneity in anterior cingulate cortex in major depressive disorder: A multi-voxel 1H magnetic resonance spectroscopy study.

BACKGROUND: Previous studies have shown major depressive disorder (MDD) is associated with altered neuro-metabolites in the anterior cingulate cortex (ACC). However, the regional metabolic heterogeneity in the ACC in individuals with MDD remains unclear. METHODS: We recruited 59 first-episode, treatment-naive young adults with MDD and 50 healthy controls who underwent multi-voxel 1H-MRS scanning at 3 T (Tesla) with voxels placed in the ACC, which was divided into two subregions, pregenual ACC (pACC) and anterior midcingulate cortex (aMCC). Between and within-subjects metabolite concentration variations were analyzed with SPSS. RESULTS: Compared with control subjects, patients with MDD exhibited higher glutamate (Glu) and glutamine (Gln) levels in the pACC and higher myo-inositol (MI) level in the aMCC. We observed higher Glu and Gln levels and lower N-acetyl-aspartate (NAA) level in the pACC than those in the aMCC in both MDD and healthy control (HC) groups. More importantly, the metabolite concentration gradients of Glu, Gln and NAA were more pronounced in MDD patients relative to HCs. In the MDD group, the MI level in the aMCC positively correlated with the age of onset. LIMITATIONS: The use of the relative concentration of metabolites constitutes a key study limitation. CONCLUSIONS: We observed inconsistent alterations and distribution of neuro-metabolites concentration in the pACC and aMCC, revealing regional metabolic heterogeneity of ACC in first-episode, treatment-naive young individuals with MDD. These results provided new evidence for abnormal neuro-metabolites of ACC in the pathophysiology of MDD and suggested that pACC and aMCC might play different roles in MDD.

Right Superior Frontal Gyrus Cortical Thickness in Pediatric ADHD.

OBJECTIVE: We investigated the right Superior Frontal Gyrus (right-SFG) and Anterior Cingulate Cortex (ACC) in children with ADHD and their clinical relevance with Executive Function (EF) and ADHD symptom severity. METHODS: About 26 children with ADHD and 24 typically developing children (TDC; 7‒16 years) underwent Magnetic Resonance Imaging (MRI) and completed an EF assessment battery. RESULTS: Significantly thinner right-SFG in the ADHD group was found compared to the TDC group (t (48) = 2.81, p = .007, Cohen's d = 0.84). Linear regression models showed that 12.5% of inattention, 13.6% of hyperactivity, and 9.0% of EF variance was accounted for by the right-SFG thickness. CONCLUSIONS: Differences in the right-SFG thickness were found in our ADHD group and were associated with parent ratings of inattentive and hyperactive symptoms as well with EF ratings. These results replicate previous findings of thinner right-SFG and are consistent with the delayed cortical maturation theory of ADHD.