Brain Correlates of Self-Evaluation Deficits in Schizophrenia: A Combined Functional and Structural MRI Study

Self-evaluation plays an important role in adaptive functioning and is a process that is typically impaired in patients with schizophrenia. Underlying neural mechanisms for this dysfunction may be associated with manifested psychosis. However, the brain substrates underlying this deficit are not well known. The present study used brain blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) and gray matter voxel-based morphometry to explore the functional and structural brain correlates of self-evaluation deficits in schizophrenia. Eighteen patients with schizophrenia and 17 healthy controls were recruited and asked to judge whether a set of personality-trait adjectives were appropriate for describing themselves, a familiar other, or whether the adjectives were of positive or negative valence. Patients had slower response times for negative trait attributions than controls did; responses to positive trait attributions were faster than those for negative traits among the patient group, while no differences were observed in the control group. Control subjects showed greater activation within the dorsal medial prefrontal cortex (dMPFC) and the anterior cingulate cortex (ACC) than the patient group during the self-evaluation > semantic positivity-evaluation contrast. Patients showed greater activation mainly within the posterior cingulate gyrus (PCC) as compared to controls for the other-evaluation > semantic positivity-evaluation contrast. Furthermore, gray matter volume was reduced in the MPFC, temporal lobe, cuneus, and the dorsal lateral prefrontal cortex (DLPFC) among the patient group when compared to controls. The present study adds to previous findings regarding self- and other-referential processing in schizophrenia, providing support for neurobiological models of self-reflection impairment.     

The Selective Impairment of Resting-State Functional Connectivity of the Lateral Subregion of the Frontal Pole in Schizophrenia

Objective

Although extensive resting-state functional connectivity (rsFC) changes have been reported in schizophrenia, rsFC changes of the frontal pole (FP) remain unclear. The FP contains several subregions with different connection patterns; however, it is unknown whether the FP subregions are differentially affected in schizophrenia. To explore this possibility, we compared rsFC differences of the FP subregions between schizophrenia patients and healthy controls.

Method

One hundred healthy controls and 91 patients with schizophrenia underwent resting-state functional MRI with a sensitivity-encoded spiral-in (SENSE-SPIRAL) imaging sequence to reduced susceptibility-induced signal loss and distortion. The FP was subdivided into the orbital (FPo), medial (FPm), and lateral (FPl) subregions. Mean fMRI time series were extracted for each FP subregion and entered into a seed-based rsFC analysis.

Results

The FP subregions exhibited differential rsFC patterns in both healthy controls and schizophrenia patients. Direct comparison between groups revealed reduced rsFCs between the bilateral FPl and several cognitive-related regions, including the dorsolateral prefrontal cortex, medial prefrontal cortex, anterior cingulate cortex, posterior cingulate cortex/precuneus, temporal cortex and inferior parietal lobule in schizophrenia. Although the FPl exhibited obvious atrophy, rsFC changes were unrelated to volumetric atrophy in the FPl, to duration of illness, and to antipsychotic medication dosage. No significant differences were observed in the rsFCs of other FP subregions.

Conclusion

These findings suggest a selective (the lateral subregion) functional disconnection of the FP subregions in schizophrenia.     

Dynamic Changes in Brain Activations and Functional Connectivity during Affectively Different Tactile Stimuli

In the present study, we compared brain activations produced by pleasant, neutral and unpleasant touch, to the anterior lateral surface of lower leg of human subjects. It was found that several brain regions, including the contralateral primary somatosensory area (SI), bilateral secondary somatosensory area (SII), as well as contralateral middle and posterior insula cortex were commonly activated under the three touch conditions. In addition, pleasant and unpleasant touch conditions shared a few brain regions including the contralateral posterior parietal cortex (PPC) and bilateral premotor cortex (PMC). Unpleasant touch specifically activated a set of pain-related brain regions such as contralateral supplementary motor area (SMA) and dorsal parts of bilateral anterior cingulated cortex, etc. Brain regions specifically activated by pleasant touch comprised bilateral lateral orbitofrontal cortex (OFC), posterior cingulate cortex (PCC), medial prefrontal cortex (mPFC), intraparietal cortex and left dorsal lateral prefrontal cortex (DLPFC). Using a novel functional connectivity model based on graph theory, we showed that a series of brain regions related to affectively different touch had significant functional connectivity during the resting state. Furthermore, it was found that such a network can be modulated between affectively different touch conditions.     

Functional interaction of the K-Cl cotransporter (KCC1) with the Na-K-Cl cotransporter in HEK-293 cells

We have studiedthe regulation of the K-Cl cotransporter KCC1 and its functionalinteraction with the Na-K-Cl cotransporter. K-Cl cotransporter activitywas substantially activated in HEK-293 cells overexpressing KCC1(KCC1-HEK) by hypotonic cell swelling, 50 mM external K, andpretreatment with N-ethylmaleimide(NEM). Bumetanide inhibited ⁸⁶Rbefflux in KCC1-HEK cells after cell swelling [inhibition constant (K_i) ~190µM] and pretreatment with NEM(K_i ~60 µM).Thus regulation of KCC1 is consistent with properties of the red cellK-Cl cotransporter. To investigate functional interactions between K-Cland Na-K-Cl cotransporters, we studied the relationship between Na-K-Clcotransporter activation and intracellular Cl concentration([Cl]_i). Without stimulation, KCC1-HEK cells had greater Na-K-Cl cotransporter activitythan controls. Endogenous Na-K-Cl cotransporter of KCC1-HEK cells wasactivated <2-fold by low-Cl hypotonic prestimulation, compared with10-fold activation in HEK-293 cells and >20-fold activation in cellsoverexpressing the Na-K-Cl cotransporter (NKCC1-HEK). KCC1-HEK cellshad lower resting[Cl]_i than HEK-293cells; cell volume was not different among cell lines. We found a steeprelationship between[Cl]_i and Na-K-Clcotransport activity within the physiological range, supporting aprimary role for [Cl]_iin activation of Na-K-Cl cotransport and in apical-basolateral crosstalk in ion-transporting epithelia.     

Decreased expression of Sprouty2 in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder: a correlation with BDNF expression

Background

Current theories on the pathophysiology of schizophrenia suggest altered brain plasticity such as decreased neural proliferation and migration, delayed myelination, and abnormal synaptic modeling, in the brain of subjects with schizophrenia. Though functional alterations in BDNF, which plays important role in neuroplasticity, are implicated in many abnormalities found in schizophrenia, the regulatory mechanism(s) involved in the abnormal signaling of BDNF in schizophrenia is not clear. The present study investigated whether Sprouty2, a regulator of growth factor signaling, is abnormally expressed in schizophrenia, and is associated with the changes in BDNF mRNA in this disorder. The potential effect of antipsychotic drugs on Sprouty2 expression was tested in adult rats.

Methods and Findings

Sprouty2 and BDNF gene expression were analyzed in dorsolateral prefrontal cortex samples from the Stanley Array Collection. Quantitative real-time PCR analysis of RNA in 100 individuals (35 with schizophrenia, 31 with bipolar disorder, and 34 psychiatrically normal controls) showed significantly decreased expression of Sprouty2 and BDNF in both schizophrenia and bipolar disorder. Moreover, a significant correlation between these two genes existed in control, schizophrenia and bipolar subjects. Long-term treatment with antipsychotic drugs, haloperidol and olanzapine, showed differential effects on both Sprouty2 and BDNF mRNA and protein levels in the frontal cortex of rats.

Conclusion

These findings demonstrating decreased expression of Sprouty2 associated with changes in BDNF, suggest the possibility that these decreases are secondary to treatment rather than to factors that are significant in the disease process of either schizophrenia and/or bipolar disorder. Further exploration of Sprouty2-related signal transduction pathways may be helpful to design novel treatment strategies for these disorders.     

Neural Basis of Anticipatory Anxiety Reappraisals

Reappraisal is a well-known emotion regulation strategy. Recent neuroimaging studies suggest that reappraisal recruits both medial and lateral prefrontal brain regions. However, few studies have investigated neural representation of reappraisals associated with anticipatory anxiety, and the specific nature of the brain activity underlying this process remains unclear. We used functional magnetic resonance imaging (fMRI) to investigate neural activity associated with reappraisals of transient anticipatory anxiety. Although transient anxiety activated mainly subcortical regions, reappraisals targeting the anxiety were associated with increased activity in the medial and lateral prefrontal regions (including the orbitofrontal and anterior cingulate cortices). Reappraisal decreased fear circuit activity (including the amygdala and thalamus). Correlational analysis demonstrated that reductions in subjective anxiety associated with reappraisal were correlated with orbitofrontal and anterior cingulate cortex activation. Reappraisal recruits medial and lateral prefrontal regions; particularly the orbitofrontal and anterior cingulate cortices are associated with successful use of this emotion regulation strategy.     

GAD1 mRNA expression and DNA methylation in prefrontal cortex of subjects with schizophrenia

Dysfunction of prefrontal cortex in schizophrenia includes changes in GABAergic mRNAs, including decreased expression of GAD1, encoding the 67 kDa glutamate decarboxylase (GAD67) GABA synthesis enzyme. The underlying molecular mechanisms remain unclear. Alterations in DNA methylation as an epigenetic regulator of gene expression are thought to play a role but this hypothesis is difficult to test because no techniques are available to extract DNA from GAD1 expressing neurons efficiently from human postmortem brain. Here, we present an alternative approach that is based on immunoprecipitation of mononucleosomes with anti-methyl-histone antibodies differentiating between sites of potential gene expression as opposed to repressive or silenced chromatin. Methylation patterns of CpG dinucleotides at the GAD1 proximal promoter and intron 2 were determined for each of the two chromatin fractions separately, using a case-control design for 14 schizophrenia subjects affected by a decrease in prefrontal GAD1 mRNA levels. In controls, the methylation frequencies at CpG dinucleotides, while overall higher in repressive as compared to open chromatin, did not exceed 5% at the proximal GAD1 promoter and 30% within intron 2. Subjects with schizophrenia showed a significant, on average 8-fold deficit in repressive chromatin-associated DNA methylation at the promoter. These results suggest that chromatin remodeling mechanisms are involved in dysregulated GABAergic gene expression in schizophrenia.     

Altered Resting-State Functional Connectivity of the Frontal-Striatal Reward System in Social Anxiety Disorder

We investigated differences in the intrinsic functional brain organization (functional connectivity) of the human reward system between healthy control participants and patients with social anxiety disorder. Functional connectivity was measured in the resting-state via functional magnetic resonance imaging (fMRI). 53 patients with social anxiety disorder and 33 healthy control participants underwent a 6-minute resting-state fMRI scan. Functional connectivity of the reward system was analyzed by calculating whole-brain temporal correlations with a bilateral nucleus accumbens seed and a ventromedial prefrontal cortex seed. Patients with social anxiety disorder, relative to the control group, had (1) decreased functional connectivity between the nucleus accumbens seed and other regions associated with reward, including ventromedial prefrontal cortex; (2) decreased functional connectivity between the ventromedial prefrontal cortex seed and lateral prefrontal regions, including the anterior and dorsolateral prefrontal cortices; and (3) increased functional connectivity between both the nucleus accumbens seed and the ventromedial prefrontal cortex seed with more posterior brain regions, including anterior cingulate cortex. Social anxiety disorder appears to be associated with widespread differences in the functional connectivity of the reward system, including markedly decreased functional connectivity between reward regions and between reward regions and lateral prefrontal cortices, and markedly increased functional connectivity between reward regions and posterior brain regions.     

Dissociated Grey Matter Changes with Prolonged Addiction and Extended Abstinence in Cocaine Users

Extensive evidence indicates that current and recently abstinent cocaine abusers compared to drug-naïve controls have decreased grey matter in regions such as the anterior cingulate, lateral prefrontal and insular cortex. Relatively little is known, however, about the persistence of these deficits in long-term abstinence despite the implications this has for recovery and relapse. Optimized voxel based morphometry was used to assess how local grey matter volume varies with years of drug use and length of abstinence in a cross-sectional study of cocaine users with various durations of abstinence (1–102 weeks) and years of use (0.3–24 years). Lower grey matter volume associated with years of use was observed for several regions including anterior cingulate, inferior frontal gyrus and insular cortex. Conversely, higher grey matter volumes associated with abstinence duration were seen in non-overlapping regions that included the anterior and posterior cingulate, insular, right ventral and left dorsal prefrontal cortex. Grey matter volumes in cocaine dependent individuals crossed those of drug-naïve controls after 35 weeks of abstinence, with greater than normal volumes in users with longer abstinence. The brains of abstinent users are characterized by regional grey matter volumes, which on average, exceed drug-naïve volumes in those users who have maintained abstinence for more than 35 weeks. The asymmetry between the regions showing alterations with extended years of use and prolonged abstinence suggest that recovery involves distinct neurobiological processes rather than being a reversal of disease-related changes. Specifically, the results suggest that regions critical to behavioral control may be important to prolonged, successful, abstinence.     

The Na-K-Cl Cotransporters

The Na-K-Cl cotransporters are a class of membrane proteins that transport Na, K, and Cl ions into and out of a wide variety of epithelial and nonepithelial cells. The transport process mediated by Na-K-Cl cotransporters is characterized by electroneutrality (almost always with stoichiometry of 1Na:1K:2Cl) and inhibition by the loop diuretics bumetanide, benzmetanide, and furosemide. Presently, two distinct Na-K-Cl cotransporter isoforms have been identified by cDNA cloning and expression; genes encoding these two isoforms are located on different chromosomes and their gene products share approximately 60% amino acid sequence identity. The NKCC1 (CCC1, BSC2) isoform is present in a wide variety of tissues; most epithelia containing NKCC1 are secretory epithelia with the Na-K-Cl cotransporter localized to the basolateral membrane. By contrast, NKCC2 (CCC2, BSC1) is found only in the kidney, localized to the apical membrane of the epithelial cells of the thick ascending limb of Henle's loop and of the macula densa. Mutations in the NKCC2 gene result in Bartter's syndrome, an inherited disease characterized by hypokalemic metabolic alkalosis, hypercalciuria, salt wasting, and volume depletion. The two Na-K-Cl cotransporter isoforms are also part of a superfamily of cation-chloride cotransporters, which includes electroneutral K-Cl and Na-Cl cotransporters. Na-K-Cl cotransporter activity is affected by a large variety of hormonal stimuli as well as by changes in cell volume; in many tissues this regulation (particularly of the NKCCl isoform) occurs through direct phosphorylation/dephosphorylation of the cotransport protein itself though the specific protein kinases involved remain unknown. An important regulator of cotransporter activity in secretory epithelia and other cells as well is intracellular [Cl] ([Cl]_i), with a reduction in [Cl]_i being the apparent means by which basolateral Na-K-Cl cotransport activity is increased and thus coordinated with that of stimulated apical Cl channels in actively secreting epithelia.     

DARPP-32 and NCS-1 Expression is not Altered in Brains of Rats Treated with Typical or Atypical Antipsychotics

Dopamine-mediated neurotransmission imbalances are associated with several psychiatry illnesses, such as schizophrenia. Recently it was demonstrated that two proteins involved in dopamine signaling are altered in prefrontal cortex (PFC) of schizophrenic patients. DARPP-32 is a key downstream effector of intracellular signaling pathway and is downregulated in PFC of schizophrenic subjects. NCS-1 is a neuronal calcium sensor that can inhibit dopamine receptor D₂ internalization and is upregulated in PFC of schizophrenic subjects. It is well known that dopamine D₂ receptor is the main target of antipsychotic. Therefore, our purpose was to study if chronic treatment with typical or atypical antipsychotics induced alterations in DARPP-32 and NCS-1 expression in five brain regions: prefrontal cortex, hippocampus, striatum, cortex and cerebellum. We did not find any changes in DARPP-32 and NCS-1 protein expression in any brain region investigated.     

Response inhibition during cue reactivity in problem gamblers: an fMRI study

Disinhibition over drug use, enhanced salience of drug use and decreased salience of natural reinforcers are thought to play an important role substance dependence. Whether this is also true for pathological gambling is unclear. To understand the effects of affective stimuli on response inhibition in problem gamblers (PRGs), we designed an affective Go/Nogo to examine the interaction between response inhibition and salience attribution in 16 PRGs and 15 healthy controls (HCs).Four affective blocks were presented with Go trials containing neutral, gamble, positive or negative affective pictures. The No-Go trials in these blocks contained neutral pictures. Outcomes of interest included percentage of impulsive errors and mean reaction times in the different blocks. Brain activity related to No-Go trials was assessed to measure response inhibition in the various affective conditions and brain activity related to Go trials was assessed to measure salience attribution.PRGs made fewer errors during gamble and positive trials than HCs, but were slower during all trials types. Compared to HCs, PRGs activated the dorsolateral prefrontal cortex, anterior cingulate and ventral striatum to a greater extent while viewing gamble pictures. The dorsal lateral and inferior frontal cortex were more activated in PRGs than in HCs while viewing positive and negative pictures. During neutral inhibition, PRGs were slower but similar in accuracy to HCs, and showed more dorsolateral prefrontal and anterior cingulate cortex activity. In contrast, during gamble and positive pictures PRGs performed better than HCs, and showed lower activation of the dorsolateral and anterior cingulate cortex.This study shows that gambling-related stimuli are more salient for PRGs than for HCs. PRGs seem to rely on compensatory brain activity to achieve similar performance during neutral response inhibition. A gambling-related or positive context appears to facilitate response inhibition as indicated by lower brain activity and fewer behavioural errors in PRGs.     

Developmental regulation of the neuronal-specific isoform of K-Cl cotransporter KCC2 in postnatal rat brains.

We examined the expression of the KCC2 isoform of the K-Cl cotransporter in the developing and adult brain, using an affinity-purified antibody directed against a unique region of the KCC2 protein. Expression was shown to be limited to neurons at the cell bodies and cell processes in the hippocampus and cerebellum. Expression seemed to be the highest at the end of processes that originated from the CA1 pyramidal cells. Developmental up-regulation of KCC2 expression was demonstrated in the entire rat brain by Northern and Western blot analyses, and in the hippocampus by immunofluorescence. Level of KCC2 expression was minimal at birth and increased significantly during postnatal development. This pattern of expression was opposite to the one of the Na-K-2Cl cotransporter that is highly expressed in immature brain and decreases during development. The up-regulation of the K-Cl cotransporter expression is consistent with the developmental down-regulation of the intracellular Cl- concentration in neurons. The level of intracellular Cl-, in turn, determines the excitatory versus inhibitory response of the neurotransmitter gamma-aminobutyric acid in the immature versus mature brain. Finally, KCC2 expression was shown in dorsal root ganglion neurons, demonstrating that expression of the cotransporter is not strictly confined to central nervous system neurons.     

Possible role of cingulate cortex in regulating sexual behavior in male rats: effects of lesions and cuts.

The role of the cingulate cortex in regulating male sexual behavior was studied in testosterone propionate-treated castrated male rats. Males with lesions in the anterior part of the cingulate cortex showed lower levels of mount, intromission and ejaculation activities than sham-operated control males and males with lesions in the posterior part of the cingulate cortex or the frontal cortex. In male rats in which lateral connections of the anterior cingulate cortex were bilaterally interrupted by sagittal cuts, the sexual activity was much lower than in the control rats, being comparable to that of the anterior cingulate cortex lesion group, but transection of the anterior connections by a transverse cut made in the anterior part of the anterior cingulate had no effect. These results suggest that the anterior cingulate cortex and its lateral connections are critical in regulating male sexual behavior in male rats.     

Frontal cortex and reward-guided learning and decision-making

Reward-guided decision-making and learning depends on distributed neural circuits with many components. Here we focus on recent evidence that suggests four frontal lobe regions make distinct contributions to reward-guided learning and decision-making: the lateral orbitofrontal cortex, the ventromedial prefrontal cortex and adjacent medial orbitofrontal cortex, anterior cingulate cortex, and the anterior lateral prefrontal cortex. We attempt to identify common themes in experiments with human participants and with animal models, which suggest roles that the areas play in learning about reward associations, selecting reward goals, choosing actions to obtain reward, and monitoring the potential value of switching to alternative courses of action.     

Deficiency of sterol regulatory element‐binding protein‐1c induces schizophrenia‐like behavior in mice

Schizophrenia is a hereditary disease that approximately 1% of the worldwide population develops. Many studies have investigated possible underlying genes related to schizophrenia. Recently, clinical studies suggested sterol regulatory element‐binding protein (SREBP) as a susceptibility gene in patients with schizophrenia. SREBP controls cellular lipid homeostasis by three isoforms: SREBP‐1a, SREBP‐1c and SREBP‐2. This study used SREBP‐1c knockout (KO) mice to examine whether a deficiency in SREBP‐1c would affect their emotional and psychiatric behaviors. Altered mRNA expression in genes downstream from SREBP‐1c was confirmed in the brains of SREBP‐1c KO mice. Schizophrenia‐like behavior, including hyperactivity during the dark phase, depressive‐like behavior, aggressive behavior and deficits in social interaction and prepulse inhibition, was observed in SREBP‐1c KO mice. Furthermore, increased volume of the lateral ventricle was detected in SREBP‐1c KO mice. The mRNA levels of several γ‐aminobutyric acid (GABA)‐receptor subtypes and/or glutamic acid decarboxylase 65/67 decreased in the hippocampus and medial prefrontal cortex of SREBP‐1c KO mice. Thus, SREBP‐1c deficiency may contribute to enlargement of the lateral ventricle and development of schizophrenia‐like behaviors and be associated with altered GABAergic transmission.     

Impaired GAD1 expression in schizophrenia‐related WISKET rat model with sex‐dependent aggressive behavior and motivational deficit

After peri‐adolescence isolation rearing (IS) and subchronic ketamine (KET) treatment, adult, selectively bred Wistar rats (named WISKET) mimic abnormal behaviors reminiscent of human schizophrenia, including reduced prepulse‐inhibition of startle reflex, disturbances in cognition, locomotor activity and thermoregulation, decreased pain sensitivity and electrophysiological alterations. To further validate our WISKET rat line, regarding its translational utility in schizophrenia research, we examined their social behavior and introduced a short and simple holeboard (HB)‐like test to investigate their motivational deficit that predicts the cognitive disturbance. Sex‐dependent alterations in schizophrenia may yield important insights into its etiology; thus, male and female WISKET rats were also investigated and compared with their naive Wistar counterparts. Considering the contribution of the hippocampal and cortical GABAergic inhibitory circuitry in these behavioral alterations, molecular‐biology studies were also performed regarding the GAD1 gene products. Impaired social activity with increased aggression, stress‐related behavior, active social withdrawal, motivation deficit and decreased exploration were observed, especially in male WISKET rats, compared with Wistar ones and their corresponding females. These alterations were accompanied by sex‐dependent alterations regarding GAD67 mRNA and protein expression in the prefrontal cortex and hippocampus. In conclusion, the WISKET animals are valuable tools for animal‐based preclinical drug discovery studies for predictive screening of novel compounds improving negative symptoms with potential antipsychotic efficacy.     

GABA Transporter-1 Deficiency Confers Schizophrenia-Like Behavioral Phenotypes

The mechanism underlying the pathogenesis of schizophrenia remains poorly understood. The hyper-dopamine and hypo-NMDA receptor hypotheses have been the most enduring ideas. Recently, emerging evidence implicates alterations of the major inhibitory system, GABAergic neurotransmission in the schizophrenic patients. However, the pathophysiological role of GABAergic system in schizophrenia still remains dubious. In this study, we took advantage of GABA transporter 1 (GAT1) knockout (KO) mouse, a unique animal model with elevated ambient GABA, to study the schizophrenia-related behavioral abnormalities. We found that GAT1 KO mice displayed multiple behavioral abnormalities related to schizophrenic positive, negative and cognitive symptoms. Moreover, GAT1 deficiency did not change the striatal dopamine levels, but significantly enhanced the tonic GABA currents in prefrontal cortex. The GABA_A receptor antagonist picrotoxin could effectively ameliorate several behavioral defects of GAT1 KO mice. These results identified a novel function of GAT1, and indicated that the elevated ambient GABA contributed critically to the pathogenesis of schizophrenia. Furthermore, several commonly used antipsychotic drugs were effective in treating the locomotor hyperactivity in GAT1 KO mice, suggesting the utility of GAT1 KO mice as an alternative animal model for studying schizophrenia pathogenesis and developing new antipsychotic drugs.     

Temporal Dynamics of Stress-Induced Alternations of Intrinsic Amygdala Connectivity and Neuroendocrine Levels

Stress-induced changes in functional brain connectivity have been linked to the etiology of stress-related disorders. Resting state functional connectivity (rsFC) is especially informative in characterizing the temporal trajectory of glucocorticoids during stress adaptation. Using the imaging Maastricht Acute Stress Test (iMAST), we induced acute stress in 39 healthy volunteers and monitored the neuroendocrine stress levels during three runs of resting state functional magnetic resonance imaging (rs-fMRI): before (run 1), immediately following (run 2), and 30min after acute stress (run 3). The iMAST resulted in strong increases in cortisol levels. Whole-brain analysis revealed that acute stress (run 2 - 1) was characterized by changes in connectivity of the amygdala with the ventrolateral prefrontal cortex (vlPFC), ventral posterior cingulate cortex (PCC), cuneus, parahippocampal gyrus, and culmen. Additionally, cortisol responders were characterized by enhanced amygdala - medial prefrontal cortex (mPFC) connectivity. Stress recovery (run 3 - 2) was characterized by altered amygdala connectivity with the dorsolateral prefrontal cortex (dlPFC), ventral and dorsal anterior cingulate cortex (ACC), anterior hippocampal complex, cuneus, and presupplementary motor area (preSMA). Opposite to non-responders, cortisol responders were characterized by enhanced amygdala connectivity with the anterior hippocampal complex and parahippocampal gyrus, and reduced connectivity with left dlPFC, dACC, and culmen during early recovery. Acute stress responding and recovery are thus associated with changes in the functional connectivity of the amygdala network. Our findings show that these changes may be regulated via stress-induced neuroendocrine levels. Defining stress-induced neuronal network changes is pertinent to developing treatments that target abnormal neuronal activity.