Person-specific and precision neuroimaging: Current methods and future directions.

Most neuroimaging studies of brain function analyze data in normalized space to identify regions of common activation across participants. These studies treat interindividual differences in brain organization as noise, but this approach can obscure important information about the brain's functional architecture. Recently, a number of studies have adopted a person-specific approach that aims to characterize these individual differences and explore their reliability and implications for behavior. A subset of these studies has taken a precision imaging approach that collects multiple hours of data from each participant to map brain function on a finer scale. In this review, we provide a broad overview of how person-specific and precision imaging techniques have used resting-state measures to examine individual differences in the brain's organization and their impact on behavior, followed by how task-based activity continues to add detail to these discoveries. We argue that person-specific and precision approaches demonstrate substantial promise in uncovering new details of the brain's functional organization and its relationship to behavior in many areas of cognitive neuroscience. We also discuss some current limitations in this new field and some new directions it may take.

Glutathione and glutamate in schizophrenia: a 7T MRS study.

In schizophrenia, abnormal neural metabolite concentrations may arise from cortical damage following neuroinflammatory processes implicated in acute episodes. Inflammation is associated with increased glutamate, whereas the antioxidant glutathione may protect against inflammation-induced oxidative stress. We hypothesized that patients with stable schizophrenia would exhibit a reduction in glutathione, glutamate, and/or glutamine in the cerebral cortex, consistent with a post-inflammatory response, and that this reduction would be most marked in patients with "residual schizophrenia", in whom an early stage with positive psychotic symptoms has progressed to a late stage characterized by long-term negative symptoms and impairments. We recruited 28 patients with stable schizophrenia and 45 healthy participants matched for age, gender, and parental socio-economic status. We measured glutathione, glutamate and glutamine concentrations in the anterior cingulate cortex (ACC), left insula, and visual cortex using 7T proton magnetic resonance spectroscopy (MRS). Glutathione and glutamate were significantly correlated in all three voxels. Glutamine concentrations across the three voxels were significantly correlated with each other. Principal components analysis (PCA) produced three clear components: an ACC glutathione-glutamate component; an insula-visual glutathione-glutamate component; and a glutamine component. Patients with stable schizophrenia had significantly lower scores on the ACC glutathione-glutamate component, an effect almost entirely leveraged by the sub-group of patients with residual schizophrenia. All three metabolite concentration values in the ACC were significantly reduced in this group. These findings are consistent with the hypothesis that excitotoxicity during the acute phase of illness leads to reduced glutathione and glutamate in the residual phase of the illness.

Network segregation varies with neural distinctiveness in sensorimotor cortex.

Normal aging is associated with declines in sensorimotor function. Previous studies have linked age-related behavioral declines to decreases in neural differentiation (i.e., dedifferentiation), including decreases in the distinctiveness of neural activation patterns and in the segregation of large-scale neural networks at rest. However, no studies to date have explored the relationship between these two neural measures and whether they explain the same aspects of behavior. To investigate these issues, we collected a battery of sensorimotor behavioral measures in older and younger adults and estimated (a) the distinctiveness of neural representations in sensorimotor cortex and (b) sensorimotor network segregation in the same participants. Consistent with prior findings, sensorimotor representations were less distinct and sensorimotor resting state networks were less segregated in older compared to younger adults. We also found that participants with the most distinct sensorimotor representations exhibited the most segregated sensorimotor networks. However, only sensorimotor network segregation was associated with individual differences in sensorimotor performance, particularly in older adults. These novel findings link network segregation to neural distinctiveness, but also suggest that network segregation may play a larger role in maintaining sensorimotor performance with age.

Independent Components of Neural Activation Associated with 100 Days of Cognitive Training.

Some cognitive training studies have reported working memory benefits that generalize beyond the trained tasks, whereas others have only found task-specific training effects. What brain networks are associated with general training effects, rather than task-specific effects? We investigated this question in the context of working memory training using the COGITO data set, a longitudinal project including behavioral assessments before and after 100 days of cognitive training in 101 younger (20-31 years) and 103 older (65-80 years) adults. Pre- and postassessments included verbal, numerical, and spatial measures of working memory. It was therefore possible to assess training effects on working memory at a general latent ability level. Previous analyses of these data found training-related improvements on this latent working memory factor in both young and old participants. fMRI data were collected from a subsample of participants (24 young and 15 old) during pre- and post-training sessions. We used independent component analysis to identify networks involved in a perceptual decision-making task performed in the scanner. We identified five task-positive components that were task-related: two frontal networks, a ventral visual network, a motor network, and a cerebellar network. Pre-training activity of the motor network predicted latent working memory performance before training. Additionally, activity in the motor network predicted training-related changes in working memory ability. These findings suggest activity in the motor network plays a role in task-independent working memory improvements and have implications for our understanding of working memory training and for the design and implementation of future training interventions.

Neural distinctiveness declines with age in auditory cortex and is associated with auditory GABA levels.

Neural activation patterns in the ventral visual cortex in response to different categories of visual stimuli (e.g., faces vs. houses) are less selective, or distinctive, in older adults than in younger adults, a phenomenon known as age-related neural dedifferentiation. In this study, we investigated whether neural dedifferentiation extends to the auditory cortex. Inspired by previous animal work, we also investigated whether individual differences in GABA are associated with individual differences in neural distinctiveness in humans. 20 healthy young adults (ages 18-29) and 23 healthy older adults (over 65) completed a functional magnetic resonance imaging (fMRI) scan, during which neural activity was estimated while they listened to music and foreign speech. GABA levels in the auditory, ventrovisual and sensorimotor cortex were estimated in the same individuals in a separate magnetic resonance spectroscopy (MRS) scan. Relative to the younger adults, the older adults exhibited both (1) less distinct activation patterns for music vs. speech stimuli and (2) lower GABA levels in the auditory cortex. Also, individual differences in auditory GABA levels (but not ventrovisual or sensorimotor GABA levels) were associated with individual differences in neural distinctiveness in the auditory cortex in the older adults. These results demonstrate that age-related neural dedifferentiation extends to the auditory cortex and suggest that declining GABA levels may play a role in neural dedifferentiation in older adults.

Sensorimotor network segregation declines with age and is linked to GABA and to sensorimotor performance.

Aging is typically associated with declines in sensorimotor performance. Previous studies have linked some age-related behavioral declines to reductions in network segregation. For example, compared to young adults, older adults typically exhibit weaker functional connectivity within the same functional network but stronger functional connectivity between different networks. Based on previous animal studies, we hypothesized that such reductions of network segregation are linked to age-related reductions in the brain's major inhibitory transmitter, gamma aminobutyric acid (GABA). To investigate this hypothesis, we conducted graph theoretical analyses of resting state functional MRI data to measure sensorimotor network segregation in both young and old adults. We also used magnetic resonance spectroscopy to measure GABA levels in the sensorimotor cortex and collected a battery of sensorimotor behavioral measures. We report four main findings. First, relative to young adults, old adults exhibit both less segregated sensorimotor brain networks and reduced sensorimotor GABA levels. Second, less segregated networks are associated with lower GABA levels. Third, less segregated networks and lower GABA levels are associated with worse sensorimotor performance. Fourth, network segregation mediates the relationship between GABA and performance. These findings link age-related differences in network segregation to age-related differences in GABA levels and sensorimotor performance. More broadly, they suggest a neurochemical substrate of age-related dedifferentiation at the level of large-scale brain networks.

Michigan Neural Distinctiveness (MiND) study protocol: investigating the scope, causes, and consequences of age-related neural dedifferentiation.

BACKGROUND: Aging is often associated with behavioral impairments, but some people age more gracefully than others. Why? One factor that may play a role is individual differences in the distinctiveness of neural representations. Previous research has found that neural activation patterns in visual cortex in response to different visual stimuli are often more similar (i.e., less distinctive) in older vs. young participants, a phenomenon referred to as age-related neural dedifferentiation. Furthermore, older people whose neural representations are less distinctive tend to perform worse on a wide range of behavioral tasks. The Michigan Neural Distinctiveness (MiND) project aims to investigate the scope of neural dedifferentiation (e.g., does it also occur in auditory, motor, and somatosensory cortex?), one potential cause (age-related reductions in the inhibitory neurotransmitter gamma-aminobutyric acid (GABA)), and the behavioral consequences of neural dedifferentiation. This protocol paper describes the study rationale and methods being used in complete detail, but not the results (data collection is currently underway). METHODS: The MiND project consists of two studies: the main study and a drug study. In the main study, we are recruiting 60 young and 100 older adults to perform behavioral tasks that measure sensory and cognitive function. They also participate in functional MRI (fMRI), MR spectroscopy, and diffusion weighted imaging sessions, providing data on neural distinctiveness and GABA concentrations. In the drug study, we are recruiting 25 young and 25 older adults to compare neural distinctiveness, measured with fMRI, after participants take a placebo or a benzodiazepine (lorazepam) that should increase GABA activity. DISCUSSION: By collecting multimodal imaging measures along with extensive behavioral measures from the same subjects, we are linking individual differences in neurochemistry, neural representation, and behavioral performance, rather than focusing solely on group differences between young and old participants. Our findings have the potential to inform new interventions for age-related declines. TRIAL REGISTRATION: This study was retrospectively registered with the ISRCTN registry on March 4, 2019. The registration number is ISRCTN17266136 .

Lateral Prefrontal Stimulation of Active Cortex With Theta Burst Transcranial Magnetic Stimulation Affects Subsequent Engagement of the Frontoparietal Network.

BACKGROUND: A critical unanswered question about therapeutic transcranial magnetic stimulation is what patients should do during treatment to optimize its effectiveness. Here, we address this lack of knowledge in healthy participants, testing the hypotheses that stimulating the left dorsolateral prefrontal cortex (dlPFC) while participants perform a working memory task will provide stronger effects on subsequent activation, perfusion, connectivity, and performance than stimulating resting dlPFC. METHODS: After a baseline functional magnetic resonance imaging session to localize dlPFC activation and the associated frontoparietal network (FPN) engaged by an n-back task, healthy participants (N = 40, 67.5% female) underwent 3 counterbalanced sessions, separated by several weeks, during which they received intermittent theta burst stimulation (iTBS) followed by magnetic resonance imaging scans as follows: 1) iTBS to the dlPFC while resting passively (passive), 2) iTBS to the dlPFC while performing the n-back task (active), and 3) iTBS to a vertex site, while not engaged in the n-back task and resting passively (control). RESULTS: We found no difference in n-back performance between the 3 conditions. However, FPN activation was reduced while performing the n-back task in the active condition relative to the passive and control conditions. There was no differential activity in the FPN on comparing passive with control conditions, i.e., there was no effect of the site of stimulation. We found no effects of state or site of stimulation on perfusion or connectivity with the dlPFC. CONCLUSIONS: In this study, the state of the brain while receiving iTBS affected FPN activation, possibly reflecting greater efficiency of FPN network activation when participants were stimulated while engaging the FPN.

Medial Frontal Cortex GABA Concentrations in Psychosis Spectrum and Mood Disorders: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies.

BACKGROUND: Abnormalities of GABAergic (gamma-aminobutyric acidergic) systems may play a role in schizophrenia and mood disorders. Magnetic resonance spectroscopy allows for noninvasive in vivo quantification of GABA; however, studies of GABA in schizophrenia have yielded inconsistent findings. This may stem from grouping together disparate voxels from functionally heterogeneous regions. METHODS: We searched PubMed for magnetic resonance spectroscopy studies of GABA in the medial frontal cortex (MFC) in patients with schizophrenia, bipolar disorder, and depression and in individuals meeting criteria for ultra-high risk for psychosis. Voxel placements were classified as rostral-, rostral-mid-, mid-, or posterior MFC, and meta-analyses were conducted for each group for each subregion. RESULTS: Of 341 screened articles, 23 studies of schizophrenia, 6 studies of bipolar disorder, 20 studies of depression, and 7 studies of ultra-high risk met the inclusion criteria. Meta-analysis revealed lower mid- (standardized mean difference [SMD] = -0.28, 95% CI, -0.48 to -0.07, p < .01) and posterior (SMD = -0.29, 95% CI, -0.49 to -0.09, p < .01) MFC GABA in schizophrenia and increased rostral MFC GABA in bipolar disorder (SMD = 0.76, 95% CI, 0.25 to -1.25, p < .01). In depression, reduced rostral MFC GABA (SMD = -0.36, 95% CI, -0.64 to -0.08, p = .01) did not survive correction for multiple comparisons. We found no evidence for GABA differences in individuals at ultra-high risk for psychosis. CONCLUSIONS: While limited by small numbers of published studies, these results substantiate the relevance of GABA in the pathophysiology of psychosis spectrum and mood disorders and underline the importance of voxel placement.

Catatonia is associated with higher rates of negative affect amongst patients with schizophrenia and schizoaffective disorder.

Catatonia is a complex syndrome encompassing motor, behavioral, and affective symptoms seen in a significant proportion of patients with schizophrenia. There is growing evidence to suggest affective dysregulation is a salient feature of both catatonia and schizophrenia. To test the hypothesis of a linkage between affective dysregulation and catatonia in schizophrenia, we searched electronic medical records from 36,839 patients with schizophrenia, using anxiety and depression diagnoses as proxies for affective dysregulation. Catatonia was found in 4.7 % of the cohort. Analyses indicated that catatonia was significantly associated with both anxiety and depression co-morbidities: schizophrenia patients with catatonia were 1.71 times more likely to have anxiety and 1.80 times more likely to have depression than those without catatonia. Benzodiazepine usage was also 7.73 times more common in schizophrenia patients with a catatonia diagnosis than without that diagnosis. Taken together, the findings could be related to GABAergic dysfunction underlying schizophrenia, catatonia, and affective dysregulation.

Phonological processing in psychopathic offenders.

Recent research has demonstrated that psychopathic offenders exhibit dynamic cognitive and behavioral deficits on a variety of lab tasks that differentially activate left hemisphere resources. The Left Hemisphere Activation (LHA) hypothesis is a cognitive perspective that aims to address these deficits by conceptualizing psychopathy as a disorder in which behavior and cognitive processing change dynamically as a function of the differential taxation of left hemisphere resources. This study aimed to investigate whether psychopathic traits are associated with electrophysiological anomalies under conditions that place differential demands on left hemisphere language processing systems. We examined in a sample of 43 incarcerated indivdiuals the evocation of the N320, an event-related potential (ERP) elicited by nontarget stimuli during a phonological/phonetic decision task that has been shown to elicit greater activation and cognitive processing within the left hemisphere than the right hemisphere. Findings for a subsample of 18 offenders low in psychopathic traits were generally consistent with previous findings in healthy individuals, suggesting similar electrophysiological activity during phonological processing. However, psychopathic traits impacted the amplitude of the N320. Higher levels of psychopathic traits were associated with reduced left-lateralization in phonological processing as well as enhanced ERP differentiation between pronounceable and nonpronounceable stimuli. These findings provide physiological evidence of a relationship between psychopathic traits and anomalous language processing at the phonological level of word processing.

Regional Brain Correlates of Beta Bursts in Health and Psychosis: A Concurrent Electroencephalography and Functional Magnetic Resonance Imaging Study.

BACKGROUND: There is emerging evidence for abnormal beta oscillations in psychosis. Beta oscillations are likely to play a key role in the coordination of sensorimotor information that is crucial to healthy mental function. Growing evidence suggests that beta oscillations typically manifest as transient beta bursts that increase in probability following a motor response, observable as post-movement beta rebound. Evidence indicates that post-movement beta rebound is attenuated in psychosis, with greater attenuation associated with greater symptom severity and impairment. Delineating the functional role of beta bursts therefore may be key to understanding the mechanisms underlying persistent psychotic illness. METHODS: We used concurrent electroencephalography and functional magnetic resonance imaging to identify blood oxygen level-dependent correlates of beta bursts during the n-back working memory task and intervening rest periods in healthy control participants (n = 30) and patients with psychosis (n = 48). RESULTS: During both task blocks and intervening rest periods, beta bursts phasically activated regions implicated in task-relevant content while suppressing currently tonically active regions. Patients showed attenuated post-movement beta rebound that was associated with persisting disorganization symptoms as well as impairments in cognition and role function. Patients also showed greater task-related reductions in overall beta burst rate and showed greater, more extensive, beta burst-related blood oxygen level-dependent activation. CONCLUSIONS: Our evidence supports a model in which beta bursts reactivate latently maintained sensorimotor information and are dysregulated and inefficient in psychosis. We propose that abnormalities in the mechanisms by which beta bursts coordinate reactivation of contextually appropriate content can manifest as disorganization, working memory deficits, and inaccurate forward models and may underlie a core deficit associated with persisting symptoms and impairment.

GABA levels in ventral visual cortex decline with age and are associated with neural distinctiveness.

Age-related neural dedifferentiation-a decline in the distinctiveness of neural representations in the aging brain-has been associated with age-related declines in cognitive abilities. But why does neural distinctiveness decline with age? Based on prior work in nonhuman primates and more recent work in humans, we hypothesized that the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) declines with age and is associated with neural dedifferentiation in older adults. To test this hypothesis, we used magnetic resonance spectroscopy (MRS) to measure GABA and functional MRI (fMRI) to measure neural distinctiveness in the ventral visual cortex in a set of older and younger participants. Relative to younger adults, older adults exhibited lower GABA levels and less distinct activation patterns for faces and houses in the ventral visual cortex. Furthermore, individual differences in GABA within older adults positively predicted individual differences in neural distinctiveness. These results provide novel support for the view that age-related reductions of GABA contribute to age-related reductions in neural distinctiveness (i.e., neural dedifferentiation) in the human ventral visual cortex.

Effective connectivity of the right anterior insula in schizophrenia: The salience network and task-negative to task-positive transition.

Triple network dysfunction theory of schizophrenia postulates that the interaction between the default-mode and the fronto-parietal executive network is disrupted by aberrant salience signals from the right anterior insula (rAI). To date, it is not clear how the proposed resting-state disruption translates to task-processing inefficiency in subjects with schizophrenia. Using a contiguous resting and 2-back task performance fMRI paradigm, we quantified the change in effective connectivity that accompanies rest-to-task state transition in 29 clinically stable patients with schizophrenia and 31 matched healthy controls. We found an aberrant task-evoked increase in the influence of the rAI to both executive (Cohen's d = 1.35, p = 2.8 × 10-6) and default-mode (Cohen's d = 1.22, p = 1.5 × 10-5) network regions occur in patients when compared to controls. In addition, the effective connectivity from middle occipital gyrus (dorsal visual cortex) to insula is also increased in patients as compared with healthy controls. Aberrant insula to executive network influence is pronounced in patients with more severe negative symptom burden. These findings suggest that control signals from rAI are abnormally elevated and directed towards both task-positive and task-negative brain regions, when task-related demands arise in schizophrenia. This aberrant, undiscriminating surge in salience signalling may disrupt contextually appropriate allocation of resources in the neuronal workspace in patients with schizophrenia.

Temporal Dynamics of Corticocortical Inhibition in Human Visual Cortex: A TMS Study.

Paired-pulse transcranial magnetic stimulation (ppTMS) has been used extensively to probe local facilitatory and inhibitory function in motor cortex. We previously developed a reliable ppTMS method to investigate these functions in visual cortex and found reduced thresholds for net intracortical inhibition compared to motor cortex. The current study used this method to investigate the temporal dynamics of local facilitatory and inhibitory networks in visual cortex in 28 healthy subjects. We measured the size of the visual disturbance (phosphene) evoked by stimulating visual cortex with a fixed intensity, supra-threshold test stimulus (TS) when that TS was preceded by a sub-threshold conditioning stimulus (CS). We manipulated the inter-stimulus interval (ISI) and assessed how the size of the phosphene elicited by the fixed-intensity TS changed as a function of interval for two different CS intensities (45% and 75% of phosphene threshold). At 45% of threshold, the CS produced uniform suppression of the phosphene elicited by the TS across ISIs ranging from 2 to 200 ms. At 75% of threshold, the CS did not have a significant effect on phosphene size across the 2-15 ms intervals. Intervals of 50-200 ms exhibited statistically significant suppression of phosphenes, however, suppression was not uniform with some subjects demonstrating no change or facilitation. This study demonstrates that the temporal dynamics of local inhibitory and facilitatory networks are different across motor and visual cortex and that optimal parameters to index local inhibitory and facilitatory influences in motor cortex are not necessarily optimal for visual cortex. We refer to the observed inhibition as visual cortex inhibition (VCI) to distinguish it from the phenomenon reported in motor cortex.

Probing short-latency cortical inhibition in the visual cortex with transcranial magnetic stimulation: A reliability study.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a non-invasive method to stimulate localized brain regions. Despite widespread use in motor cortex, TMS is seldom performed in sensory areas due to variable, qualitative metrics. OBJECTIVE: Assess the reliability and validity of tracing phosphenes, and to investigate the stimulation parameters necessary to elicit decreased visual cortex excitability with paired-pulse TMS at short inter-stimulus intervals. METHODS: Across two sessions, single and paired-pulse recruitment curves were derived by having participants outline elicited phosphenes and calculating resulting average phosphene sizes. RESULTS: Phosphene size scaled with stimulus intensity, similar to motor cortex. Paired-pulse recruitment curves demonstrated inhibition at lower conditioning stimulus intensities than observed in motor cortex. Reliability was high across sessions. CONCLUSIONS: TMS-induced phosphenes are a valid and reliable tool for measuring cortical excitability and inhibition in early visual areas. Our results also provide appropriate stimulation parameters for measuring short-latency intracortical inhibition in visual cortex.

Age-Related Declines in Occipital GABA are Associated with Reduced Fluid Processing Ability.

RATIONALE AND OBJECTIVES: Healthy aging is associated with pervasive declines in cognitive, motor, and sensory functioning. There are, however, substantial individual differences in behavioral performance among older adults. Several lines of animal research link age-related reductions of gamma-aminobutyric acid (GABA), the brain's primary inhibitory neurotransmitter, to age-related cognitive, motor, and sensory decline. Our study used proton magnetic resonance spectroscopy (MRS) at 3T to explore whether occipital GABA declines with age in humans and whether individual differences in occipital GABA are linked to individual differences in fluid processing ability. MATERIALS AND METHODS: We used a MEGA-PRESS sequence that combines frequency spectral editing with a point-resolved spectroscopy sequence to quantify GABA. Spectra were obtained from a 30 × 30 × 25 mm voxel placed in the occipital cortex of 20 young adults (mean age 20.7 years) and 18 older adults (mean age 76.5 years). Participants also performed 11 fluid processing tasks outside the scanner, the results of which were z-scored and averaged to calculate a summary measure of fluid processing ability. Regression analysis was employed to determine the relationship between GABA concentrations in the occipital cortex and a summary measure of fluid processing ability. RESULTS: Occipital GABA was significantly lower in older participants compared to the younger participants. We also observed a significant positive relationship between occipital GABA and fluid processing ability. In fact, higher GABA was associated with better task performance in 10 of the 11 tasks. CONCLUSION: These findings suggest that GABA levels decline with age in humans and are associated with declines in fluid processing ability.

Reduced event-related low frequency EEG activity in patients with early onset schizophrenia and their unaffected siblings.

Low-frequency oscillations in the electroencephalogram (EEG) have been found to be abnormal in patients with schizophrenia. It is unclear, however, whether these abnormalities are related to severity of illness or are a marker for risk. This study investigated total and evoked theta and delta activity in schizophrenia patients, unaffected siblings, and healthy controls (HCs). EEG data were recorded whilst 24 individuals with schizophrenia, 26 unaffected siblings of individuals with schizophrenia and 26 healthy control participants completed a Go/No-Go task. Event-related total activity and evoked theta and delta activity were calculated for correct hits (CH), failed inhibitions (FI) and correct inhibitions (CI) trials. Patients displayed significantly less total delta, evoked delta, total theta and evoked theta activity when compared with healthy controls. Unaffected siblings displayed abnormalities of evoked delta, but other measures were similar to those in control participants. The findings of this study add to evidence that abnormal low-frequency EEG oscillations contribute to impairments in information processing seen in schizophrenia. These findings also suggest abnormal evoked delta oscillations are associated with an increased familial risk of developing the disorder.

Neural primacy of the salience processing system in schizophrenia.

For effective information processing, two large-scale distributed neural networks appear to be critical: a multimodal executive system anchored on the dorsolateral prefrontal cortex (DLPFC) and a salience system anchored on the anterior insula. Aberrant interaction among distributed networks is a feature of psychiatric disorders such as schizophrenia. We used whole-brain Granger causal modeling using resting fMRI and observed a significant failure of both the feedforward and reciprocal influence between the insula and the DLPFC in schizophrenia. Further, a significant failure of directed influence from bilateral visual cortices to the insula was also seen in patients. These findings provide compelling evidence for a breakdown of the salience-execution loop in the clinical expression of psychosis. In addition, this offers a parsimonious explanation for the often-observed "frontal inefficiency," the failure to recruit prefrontal system when salient or novel information becomes available in patients with schizophrenia.