Fear conditioning and extinction in alcohol dependence: Evidence for abnormal amygdala reactivity.

Fear conditioning and extinction (FCE) are vital processes in adaptive emotion regulation and disrupted in anxiety disorders. Despite substantial comorbidity between alcohol dependence (ALC) and anxiety disorders and reports of altered negative emotion processing in ALC, neural correlates of FCE in this clinical population remain unknown. Here, we used a 2-day fear learning paradigm in 43 healthy participants and 43 individuals with ALC at the National Institutes of Health. Main outcomes of this multimodal study included structural and functional brain magnetic resonance imaging, clinical measures, as well as skin conductance responses (SCRs) to confirm differential conditioning. Successful FCE was demonstrated across participants by differential SCRs in the conditioning phase and no difference in SCRs to the conditioned stimuli in the extinction phase. The ALC group showed significantly reduced blood oxygenation level-dependent responses in the right amygdala during conditioning (Cohen's d = .89, P(FWE) = .037) and in the left amygdala during fear renewal (Cohen's d = .68, P(FWE) = .039). Right amygdala activation during conditioning was significantly correlated with ALC severity (r = .39, P(Bonferroni) = .009), depressive symptoms (r = .37, P(Bonferroni) = .015), trait anxiety (r = .41, P(Bonferroni) = .006), and perceived stress (r = .45, P(Bonferroni) = .002). Our data suggest that individuals with ALC have dysregulated fear learning, in particular, dysregulated neural activation patterns, in the amygdala. Furthermore, amygdala activation during fear conditioning was associated with ALC-related clinical measures. The FCE paradigm may be a promising tool to investigate structures involved in negative affect regulation, which might inform the development of novel treatment approaches for ALC.

Dopamine Transporter Gene Methylation is Associated with Nucleus Accumbens Activation During Reward Processing in Healthy but not Alcohol-Dependent Individuals.

BACKGROUND: Alcohol's reinforcement is mediated by dopamine signaling in the ventral striatum, which is modulated by the dopamine transporter (DAT). We hypothesized that methylomic variation in the DAT gene (DAT1/SLC6A3) affects DAT expression, thus contributing to differences in brain reward circuitry in individuals with alcohol dependence (ALC). METHODS: Blood from 45 recently detoxified ALC and 45 healthy control (HC) individuals was used to assess DNA methylation across 5 functional regions of SLC6A3. Participants completed the monetary incentive delay task in a 3-Tesla magnetic resonance imaging (MRI) scanner. Employing regression models, we examined effects of SLC6A3 methylation on nucleus accumbens (NAc) blood-oxygen-level dependent (BOLD) responses during anticipation of high/low reward/loss. RESULTS: Results showed that decreased methylation of the promoter region of SLC6A3 predicted NAc activation during high loss anticipation (p = 0.028) and low loss anticipation (at trend-level; p = 0.057) in HC but not in individuals with ALC. Specifically, percentage of methylation at 2 CpG sites, located -1,001 and -993 base pairs from the transcription start site, accounted for significant variability in NAc activation in the HC group during high (ps ≤ 0.010) and low (ps ≤ 0.006) loss anticipation. There was no effect on reward anticipation. Furthermore, promoter methylation was positively associated with age, which replicates previous findings. CONCLUSIONS: Our data suggest that methylation in the promoter region of SLC6A3 predicts NAc activation during the anticipation of monetary loss in HCs. However, this effect was not present in the ALC group, suggesting that epigenetic regulation of striatal DAT expression might be disrupted in ALC, which may contribute to previously reported differences in sensitivity to reward and punishment in this population. Alternatively, it is possible that a similar relationship in the ALC group remained undetected possibly due to methodological limitations inherent in functional MRI (e.g., poor spatial resolution, low signal-to-noise ratio) that generally restrict interpretations regarding mechanisms of epigenetic factors involved in group differences in BOLD responses. Future neuroimaging studies are needed to further elucidate the relationship between SLC6A3 methylation and NAc activation in ALC.

Insula Sensitivity to Unfairness in Alcohol Use Disorder.

AIMS: Social decision making has recently been evaluated in alcohol use disorder (AUD) using the ultimatum game (UG) task, suggesting a possible deficit in aversive emotion regulation elicited by the unfairness during this task. Despite the relevance to relapse of this possible faulty regulation, the brain correlates of the UG in AUD are unknown. METHODS: In total, 23 AUD and 27 healthy controls (HC) played three consecutive fMRI runs of the UG, while behavioral and brain responses were recorded. RESULTS: Overall, acceptance rate of unfair offers did not differ between groups, but there was a difference in the rate of behavioral change across runs. We found significant anterior insula (aINS) activation in both groups for both fair and unfair conditions, but only HC showed a trend towards increased activation during unfair vs. fair offers. There were not overall whole-brain between-group significant differences. We found a trend of signal attenuation, instead of an increase, in the aINS for AUD when compared to HC during the third run, which is consistent with our recent findings of selective insula atrophy in AUD. CONCLUSION: We found differential group temporal dynamics of behavioral response in the UG. The HC group had a low acceptance rate for unfair offers in the first two runs that increased markedly for the third run; whereas the AUD group was consistent in their rejection of unfair offers across the three runs. We found a strong significant decrease in neural response across runs for both groups. SHORT SUMMARY: This fMRI study of UG in alcohol use disorder found behavioral group differences in acceptance rate across runs, which together with significant BOLD-signal decrease across runs in UG-related regions in both groups, highlights the impairment of strategy in AUD and the effect of repetitive exposure to unfairness in this task.

Model-free functional connectivity and impulsivity correlates of alcohol dependence: a resting-state study.

Alcohol dependence is characterized by impulsiveness toward consumption despite negative consequences. Although neuro-imaging studies have implicated some regions underlying this disorder, there is little information regarding its large-scale connectivity pattern. This study investigated the within- and between-network functional connectivity (FC) in alcohol dependence and examined its relationship with clinical impulsivity measures. Using probabilistic independent component analysis on resting-state functional magnetic resonance imaging (rs-fMRI) data from 25 alcohol-dependent (AD) and 26 healthy control (HC) participants, we compared the within- and between-network FC between AD and HC. Then, the relationship between FC and impulsiveness as measured by the Barratt Impulsiveness Scale (BIS-11), the UPPS-P Impulsive Scale and the delay discounting task (DDT), was explored. Compared with HC, AD exhibited increased within-network FC in salience (SN), default mode (DMN), orbitofrontal cortex (OFCN), left executive control (LECN) and amygdala-striatum (ASN) networks. Increased between-network FC was found among LECN, ASN and SN. Between-network FC correlations were significantly negative between Negative-Urgency and OFCN pairs with right executive control network (RECN), anterior DMN (a-DMN) and posterior DMN (p-DMN) in AD. DDT was significantly correlated with the between-network FC among the LECN, a-DMN and SN in AD. These findings add evidence to the concept of altered within-network FC and also highlight the role of between-network FC in the pathophysiology of AD. Additionally, this study suggests differential neurobiological bases for different clinical measures of impulsivity that may be used as a systems-level biomarker for alcohol dependence severity and treatment efficacy.

Resting-state functional connectivity and presynaptic monoamine signaling in Alcohol Dependence.

Alcohol Dependence (AD) is a chronic relapsing disorder with high degrees of morbidity and mortality. While multiple neurotransmitter systems are involved in the complex symptomatology of AD, monoamine dysregulation and subsequent neuroadaptations have been long postulated to play an important role. Presynaptic monoamine transporters, such as the vesicular monoamine transporter 1 (VMAT1), are likely critical as they represent a key common entry point for monoamine regulation and may represent a shared pathway for susceptibility to AD. Excessive monoaminergic signaling as mediated by genetic variation in VMAT1 might affect functional brain connectivity in particular in alcoholics compared to controls. We conducted resting-state fMRI functional connectivity (FC) analysis using the independent component analysis (ICA) approach in 68 AD subjects and 72 controls. All subjects were genotyped for the Thr136Ile (rs1390938) variant in VMAT1. Functional connectivity analyses showed a significant increase of resting-state FC in 4 networks in alcoholics compared to controls (P < 0.05, corrected). The FC was significantly positively correlated with Alcohol Dependence Scale (ADS). The hyperfunction allele 136Ile was associated with a significantly decreased FC in the Default Mode Network, Prefrontal Cortex Network, and Executive Control Network in alcohol dependent participants (P < 0.05, corrected), but not in controls. Our data suggest that increased FC might represent a neuroadaptive mechanism relevant to AD that is furthermore mediated by genetic variation in VMAT1. The hyperfunction allele Thr136Ile might have a protective effect that is, in particular, relevant in AD by mechanism of increased monoamine transport into presynaptic storage vesicles.

Repetition of letter strings leads to activation of and connectivity with word-related regions.

Individuals learn to read by gradually recognizing repeated letter combinations. However, it is unclear how or when neural mechanisms associated with repetition of basic stimuli (i.e., strings of letters) shift to involvement of higher-order language networks. The present study investigated this question by repeatedly presenting unfamiliar letter strings in a one-back matching task during an hour-long period. Activation patterns indicated that only brain areas associated with visual processing were activated during the early period, but additional regions that are usually associated with semantic and phonological processing in inferior frontal gyrus were recruited after stimuli became more familiar. Changes in activation were also observed in bilateral superior temporal cortex, also suggestive of a shift toward a more language-based processing strategy. Connectivity analyses reveal two distinct networks that correspond to phonological and visual processing, which may reflect the indirect and direct routes of reading. The phonological route maintained a similar degree of connectivity throughout the experiment, whereas visual areas increased connectivity with language areas as stimuli became more familiar, suggesting early recruitment of the direct route. This study provides insight about plasticity of the brain as individuals become familiar with unfamiliar combinations of letters (i.e., words in a new language, new acronyms) and has implications for engaging these linguistic networks during development of language remediation therapies.

Alcohol effects on globus pallidus connectivity: Role of impulsivity and binge drinking.

Despite the harm caused by binge drinking, the neural mechanisms leading to risky and disinhibited intoxication-related behaviors are not well understood. Evidence suggests that the globus pallidus externus (GPe), a substructure within the basal ganglia, participates in inhibitory control processes, as examined in stop-signaling tasks. In fact, studies in rodents have revealed that alcohol can change GPe activity by decreasing neuronal firing rates, suggesting that the GPe may have a central role in explaining impulsive behaviors and failures of inhibition that occur during binge drinking. In this study, twenty-five healthy volunteers underwent intravenous alcohol infusion to achieve a blood alcohol level of 0.08 g/dl, which is equivalent to a binge drinking episode. A resting state functional magnetic resonance imaging scan was collected prior to the infusion and at binge-level exposure. Functional connectivity analysis was used to investigate the association between alcohol-induced changes in GPe connectivity, drinking behaviors, and impulsivity traits. We found that individuals with greater number of drinks or heavy drinking days in the recent past had greater alcohol-induced deficits in GPe connectivity, particularly to the striatum. Our data also indicated an association between impulsivity and alcohol-induced deficits in GPe-frontal/precentral connectivity. Moreover, alcohol induced changes in GPe-amygdala circuitry suggested greater vulnerabilities to stress-related drinking in some individuals. Taken together, these findings suggest that alcohol may interact with impulsive personality traits and drinking patterns to drive alterations in GPe circuitry associated with behavioral inhibition, possibly indicating a neural mechanism by which binge drinking could lead to impulsive behaviors.

The major depressive disorder GWAS-supported variant rs10514299 in TMEM161B-MEF2C predicts putamen activation during reward processing in alcohol dependence.

Alcohol dependence (AD) frequently co-occurs with major depressive disorder (MDD). While this comorbidity is associated with an increase in disease burden, worse treatment outcomes, and greater economic costs, the underlying neurobiology remains poorly understood. A recent large-scale GWAS of MDD has identified a locus in the TMEM161B-MEF2C region (rs10514299) as a novel risk variant; however, the biological relevance of this variant has not yet been studied. Given previous reports of disrupted reward processing in both AD and MDD, we hypothesized that rs10514299 would be associated with differences in striatal BOLD responses during reward/loss anticipation in AD. DNA samples from 45 recently detoxified patients with AD and 45 healthy controls (HC) were genotyped for rs10514299. Participants performed the Monetary Incentive Delay task in a 3-Tesla MRI scanner. Effects of rs10514299 on striatal activation during anticipation of high/low reward/loss were investigated. Furthermore, we examined associations between rs10514299 and lifetime AD diagnosis in two independent clinical samples [NIAAA: n = 1858 (1123 cases, 735 controls); SAGE: n = 3838 (1848 cases, 1990 controls)], as well as its association with depression severity in a subsample of individuals with a lifetime AD diagnosis (n = 953). Patients carrying the T allele showed significantly greater putamen activation during anticipation of high reward (p = 0.014), low reward (at trend-level; p = 0.081), high loss (p = 0.024), and low loss (p = 0.046) compared to HCs. Association analyses in the NIAAA sample showed a trend-level relationship between rs10514299 and a lifetime AD diagnosis in the European American subgroup (odds ratio = 0.82, p = 0.09). This finding was not replicated in the SAGE sample. In the NIAAA sample, the T allele was significantly associated with greater depression symptom severity in individuals with a lifetime AD diagnosis (ß = 1.25, p = 0.02); this association was driven by the African American ancestry subgroup (ß = 2.11, p = 0.008). We show for the first time that the previously identified MDD risk variant rs10514299 in TMEM161B-MEF2C predicts neuronal correlates of reward processing in an AD phenotype, possibly explaining part of the shared pathophysiology and comorbidity between the disorders.

The Basal Forebrain Regulates Global Resting-State fMRI Fluctuations.

Patterns of spontaneous brain activity, typically measured in humans at rest with fMRI, are used routinely to assess the brain's functional organization. The mechanisms that generate and coordinate the underlying neural fluctuations are largely unknown. Here we investigate the hypothesis that the nucleus basalis of Meynert (NBM), the principal source of widespread cholinergic and GABAergic projections to the cortex, contributes critically to such activity. We reversibly inactivated two distinct sites of the NBM in macaques while measuring fMRI activity across the brain. We found that inactivation led to strong, regionalized suppression of shared or "global" signal components of cortical fluctuations ipsilateral to the injection. At the same time, the commonly studied resting-state networks retained their spatial structure under this suppression. The results indicate that the NBM contributes selectively to the global component of functional connectivity but plays little if any role in the specific correlations that define resting-state networks.

Structural deficits in salience network regions are associated with increased impulsivity and compulsivity in alcohol dependence.

BACKGROUND: Convergent preclinical and clinical evidence has linked the anterior insula to impulsivity and alcohol-associated compulsivity. The anterior insula is functionally connected to the anterior cingulate cortex, together comprising the major nodes of the salience network, which serves to signal salient events, including negative consequences. Clinical studies have found structural and functional alterations in the anterior insula and anterior cingulate cortices of alcohol dependent individuals. No studies have yet investigated the association between morphometric abnormalities in salience network regions and the phenotype of high levels of impulsivity and compulsivity seen in alcohol dependent individuals. METHODS: In the current study, we compared self-report impulsivity, decisional impulsivity, self-report compulsivity, and structural neuroimaging measures in a sample of alcohol dependent individuals (n=60) and a comparison group of healthy controls (n=49). From the structural magnetic resonance images, we calculated volume and cortical thickness for 6 regions of interest: left and right anterior insula, posterior insula, and anterior cingulate. RESULTS: We found that alcohol dependent individuals had smaller anterior insula and anterior cingulate volumes, as well as thinner anterior insula cortices. There were no group differences in posterior insula morphometry. Anterior insula and anterior cingulate structural measures were negatively associated with self-report impulsivity, decisional impulsivity, and compulsivity measures. CONCLUSIONS: Our results suggest that addiction endophenotypes are associated with salience network morphometry in alcohol addiction. These relationships indicate that salience network hubs represent potential treatment targets for impulse control disorders, including alcohol addiction.

The CRF1 Antagonist Verucerfont in Anxious Alcohol-Dependent Women: Translation of Neuroendocrine, But not of Anti-Craving Effects.

Blockade of corticotropin-releasing factor receptor 1 (CRF1) suppresses stress-induced alcohol seeking in rodents, but clinical translation remains. Here, we first showed that the CRF1 antagonist verucerfont potently blocks hypothalamic-pituitary adrenal (HPA) axis activation in adrenalectomized rats. We then evaluated verucerfont for its ability to block HPA axis activation and reduce stress-induced alcohol craving in alcohol-dependent patients. Anxious, alcohol-dependent women (age 21-65 years, n=39) were admitted to the NIH Clinical Center and completed withdrawal treatment before enrollment if needed. One-week single-blind placebo was followed by randomized double-blind verucerfont (350 mg per day) or placebo for 3 weeks. Verucerfont effects on the HPA axis were evaluated using the dexamethasone-CRF test. Craving was evaluated using two established protocols, one that combines a social stressor with physical alcohol cue exposure, and one that uses guided imagery to present personalized stress, alcohol, or neutral stimuli. An fMRI session examined brain responses to negative affective stimuli and alcohol cues. In contrast to our recent observations with another CRF1 antagonist, pexacerfont, verucerfont potently blocked the HPA axis response to the dexamethasone-CRF test, but left alcohol craving unaffected. Right amygdala responses to negative affective stimuli were significantly attenuated by verucerfont, but responses to alcohol-associated stimuli were increased in some brain regions, including left insula. Discontinuation rates were significantly higher in the verucerfont group. Our findings provide the first translational evidence that CRF1 antagonists with slow receptor dissociation kinetics may have increased efficacy to dampen HPA axis responses. The findings do not support a clinical efficacy of CRF1 blockade in stress-induced alcohol craving and relapse.

Neural correlates of the relationship between discourse coherence and sensory monitoring in schizophrenia.

Unusual language use is a core feature of psychosis, but the nature and significance of this are not understood. In particular, thought disorder in schizophrenia (SZ) is characterized by markedly bizarre speech, but the cognitive components that contribute to this and the brain correlates of these components are unknown. A number of studies have demonstrated language abnormalities in single word processing, but few have examined speech in SZ at the discourse level. This has been at least partly due to the difficulty in quantifying content of discourse. Recently, methods in computational linguistics have been found to be useful for detecting differences in semantic coherence during discourse between different clinical groups. We build on this work by demonstrating how these methods can be combined with funtional magnetic resonance imaging (fMRI) in order to tease apart factors that underlie free discourse and its deviations, and how they relate to brain activity. Eleven volunteers with SZ and eleven controls participated in an interview during which they were asked to talk as much as they could about 'religious belief'. These same participants underwent fMRI during a word monitoring task, during which modality of monitoring was manipulated by varying the congruence of auditory and visual stimuli. Semantic coherence scores, measured from free discourse, were examined for their relationship to brain activations during fMRI. In healthy controls, regions associated with executive function were related to coherence. In persons with SZ, coherence was mainly related to auditory and visual regions, depending on the modality of monitoring, but superior/middle temporal cortex related to coherence regardless of task. These findings are consistent with existing evidence for a role of superior temporal cortex in thought disorder, and demonstrate that computational measures of semantic content capture objective measures of coherence in speech that can be usefully related to underlying neurophysiological processes.

Working memory in attention deficit/hyperactivity disorder is characterized by a lack of specialization of brain function.

Working memory impairments are frequent in Attention Deficit/Hyperactivity Disorder (ADHD) and create problems along numerous functional dimensions. The present study utilized the Visual Serial Addition Task (VSAT) and functional magnetic resonance imaging (fMRI) to explore working memory processes in thirteen typically developing (TD) control and thirteen children with ADHD, Combined type. Analysis of Variance (ANOVA) was used to examine both main effects and interactions. Working memory-specific activity was found in TD children in the bilateral prefrontal cortex. In contrast the within-group map in ADHD did not reveal any working-memory specific regions. Main effects of condition suggested that the right middle frontal gyrus (BA6) and the right precuneus were engaged by both groups during working memory processing. Group differences were driven by significantly greater, non-working memory-specific, activation in the ADHD relative to TD group in the bilateral insula extending into basal ganglia and the medial prefrontal cortex. A region of interest analysis revealed a region in left middle frontal gyrus that was more active during working memory in TD controls. Thus, only the TD group appeared to display working memory-modulated brain activation. In conclusion, children with ADHD demonstrated reduced working memory task specific brain activation in comparison to their peers. These data suggest inefficiency in functional recruitment by individuals with ADHD represented by a poor match between task demands and appropriate levels of brain activity.

Neural changes associated with relational learning in schizophrenia.

Relational learning, which is learning the relationship among items, is impaired in schizophrenia but can be improved with training. This study investigated neural changes with functional magnetic resonance imaging before and after training on a relational learning task in schizophrenia and healthy control subjects. Despite their acquiring similar relational learning performance, the groups exhibited different neural activation patterns before and following training. Controls engaged regions within the relational learning network that included frontal, parietal, and medial temporal lobe, before and following training. Controls also exhibited activation reductions in region and spatial extent with relational learning proficiency, a commonly observed phenomenon in successful learning. In contrast, subjects with schizophrenia displayed no positive activations compared with the control condition before training. After training, subjects with schizophrenia displayed bilateral inferior parietal region activation as predicted. Contrary to hypothesis, hippocampal activation was not observed following training in schizophrenia. These findings suggest that the parietal lobe may be receptive to cognitive training interventions and that successful relational learning may be achieved in schizophrenia through the use of alternative extrahippocampal brain regions.

A lack of default network suppression is linked to increased distractibility in ADHD.

Heightened distractibility in participants with ADHD as indexed by increased reaction time (RT) variability has been hypothesized to be due to a failure to sufficiently suppress activation in the default attention network during cognitively demanding situations. The present study utilized fMRI to examine the relationship between intra-individual variability (IIV) in task RT and suppression of BOLD response in regions of the default network, using a working memory paradigm and two levels of control tasks. IIV was calculated separately for thirteen healthy control and twelve children with ADHD, Combined Type. Children with ADHD displayed significantly more RT variability than controls. Neural measures showed that although both groups displayed a pattern of increasing deactivation of the medial prefrontal cortex (PFC) with increasing task difficulty, the ADHD group was significantly less deactive than controls. Correlations between IIV and brain activation suggested that greater variability was associated with a failure to deactivate ventromedial PFC with increasing task difficulty. T-tests on brain activation between participants with ADHD with low versus high IIV implicated a similar region so that high variability was associated with greater activity in this region. These data provide support for the theory that increased distractibility in at least some participants with ADHD may be due to an inability to sufficiently suppress activity in the default attention network in response to increasing task difficulty.

Word and letter string processing networks in schizophrenia: evidence for anomalies and compensation.

Imaging studies show that in normal language correlated activity between anterior and posterior brain regions increases as the linguistic and semantic content (i.e., from false fonts, letter strings, pseudo words, to words) of stimuli increase. In schizophrenia however, disrupted functional connectivity between frontal and posterior brain regions has been frequently reported and these disruptions may change the nature of language organization. We characterized basic linguistic operations in word and letter string processing in a region-of-interest network using structural equation modeling (SEM). Healthy volunteers and volunteers with schizophrenia performed an fMRI one-back matching task with real words and consonant letter strings. We hypothesized that left hemisphere network dysfunction in schizophrenia would be present during processes dealing with linguistic/semantic content. The modeling results suggest aberrant left hemisphere function in schizophrenia, even in tasks requiring minimal access to language. Alternative mechanisms included increases in right hemisphere involvement and increased top-down influence from frontal to posterior regions.

Neural Mechanisms Underlying Learning following Semantic Mediation Treatment in a case of Phonologic Alexia.

Patients with phonologic alexia can be trained to read semantically impoverished words (e.g., functors) by pairing them with phonologically-related semantically rich words (e.g, nouns). What mechanisms underlie success in this cognitive re-training approach? Does the mechanism change if the skill is "overlearned", i.e., practiced beyond criterion? We utilized fMRI pre- and post-treatment, and after overlearning, to assess treatment-related functional reorganization in a patient with phonologic alexia, two years post left temporoparietal stroke. Pre-treatment, there were no statistically significant differences in activation profiles across the sets of words. Post-treatment, accuracy on the two trained sets improved. Compared with untrained words, reading trained words recruited larger and more significant clusters of activation in the right hemisphere, including right inferior frontal and inferior parietal cortex. Post-overlearning, with near normal performance on overlearned words, predominant activation shifted to left hemisphere regions, including perilesional activation in superior parietal lobe, when reading overlearned vs. untrained words.

Functional connectivity in fMRI: A modeling approach for estimation and for relating to local circuits.

Although progress has been made in relating neuronal events to changes in brain metabolism and blood flow, the interpretation of functional neuroimaging data in terms of the underlying brain circuits is still poorly understood. Computational modeling of connection patterns both among and within regions can be helpful in this interpretation. We present a neural network model of the ventral visual pathway and its relevant functional connections. This includes a new learning method that adjusts the magnitude of interregional connections in order to match experimental results of an arbitrary functional magnetic resonance imaging (fMRI) data set. We demonstrate that this method finds the appropriate connection strengths when trained on a model system with known, randomly chosen connection weights. We then use the method for examining fMRI results from a one-back matching task in human subjects, both healthy and those with schizophrenia. The results discovered by the learning method support previous findings of a disconnection between left temporal and frontal cortices in the group with schizophrenia and a concomitant increase of right-sided temporo-frontal connection strengths. We then demonstrate that the disconnection may be explained by reduced local recurrent circuitry in frontal cortex. This method extends currently available methods for estimating functional connectivity from human imaging data by including both local circuits and features of interregional connections, such as topography and sparseness, in addition to total connection strengths. Furthermore, our results suggest how fronto-temporal functional disconnection in schizophrenia can result from reduced local synaptic connections within frontal cortex rather than compromised interregional connections.