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1.  A Multimodal Analysis of Antipsychotic Effects on Brain Structure and Function in First-Episode Schizophrenia 
JAMA psychiatry  2015;72(3):226-234.
Recent data suggest that treatment with antipsychotics is associated with reductions in cortical gray matter in patients with schizophrenia. These findings have led to concerns about the effect of antipsychotic treatment on brain structure and function; however, no studies to date have measured cortical function directly in individuals with schizophrenia and shown antipsychotic-related reductions of gray matter.
To examine the effects of antipsychotics on brain structure and function in patients with first-episode schizophrenia, using cortical thickness measurements and administration of the AX version of the Continuous Performance Task (AX-CPT) during event-related functional magnetic resonance imaging.
This case-control cross-sectional study was conducted at the Imaging Research Center of the University of California, Davis, from November 2004 through July 2012. Participants were recruited on admission into the Early Diagnosis and Preventive Treatment Clinic, an outpatient clinic specializing in first-episode psychosis. Patients with first-episode schizophrenia who received atypical antipsychotics (medicated patient group) (n = 23) and those who received no antipsychotics (unmedicated patient group) (n = 22) and healthy control participants (n = 37) underwent functional magnetic resonance imaging using a 1.5-T scanner.
Behavioral performance was measured by trial accuracy, reaction time, and d′-context score. Voxelwise statistical parametric maps tested differences in functional activity during the AX-CPT, and vertexwise maps of cortical thickness tested differences in cortical thickness across the whole brain.
Significant cortical thinning was identified in the medicated patient group relative to the control group in prefrontal (mean reduction [MR], 0.27 mm; P < .001), temporal (MR, 0.34 mm; P = .02), parietal (MR, 0.21 mm; P = .001), and occipital (MR, 0.24 mm; P = .001) cortices. The unmedicated patient group showed no significant cortical thickness differences from the control group after clusterwise correction. The medicated patient group showed thinner cortex compared with the unmedicated patient group in the dorsolateral prefrontal cortex (DLPFC) (MR, 0.26 mm; P = .001) and temporal cortex (MR, 0.33 mm; P = .047). During the AX-CPT, both patient groups showed reduced DLPFC activity compared with the control group (P = .02 compared with the medicated group and P < .001 compared with the unmedicated group). However, the medicated patient group demonstrated higher DLPFC activation (P = .02) and better behavioral performance (P = .02) than the unmedicated patient group.
These findings highlight the complex relationship between antipsychotic treatment and the structural, functional, and behavioral deficits repeatedly identified in schizophrenia. Although short-term treatment with antipsychotics was associated with prefrontal cortical thinning, treatment was also associated with better cognitive control and increased prefrontal functional activity. This study adds important context to the growing literature on the effects of antipsychotics on the brain and suggests caution in interpreting neuroanatomical changes as being related to a potentially adverse effect on brain function.
PMCID: PMC4794273  PMID: 25588194
2.  Modafinil Effects on Middle-Frequency Oscillatory Power During Rule Selection in Schizophrenia 
Neuropsychopharmacology  2014;39(13):3018-3026.
Control-related cognitive processes such as rule selection are associated with cortical oscillations in the theta, alpha and, beta ranges, and modulated by catecholamine neurotransmission. Thus, a potential strategy for improving cognitive control deficits in schizophrenia would be to use pro-catecholamine pharmacological agents to augment these control-related oscillations. In a double-blind, placebo-controlled (within-subjects) study, we tested the effects of adjunctive single-dose modafinil 200 mg on rule-related 4–30 Hz oscillations in 23 stable schizophrenia patients, using EEG during cognitive control task performance. EEG data underwent time-frequency decomposition with Morlet wavelets to determine the power of 4–30 Hz oscillations. Modafinil (relative to placebo) enhanced oscillatory power associated with high-control rule selection in theta, alpha, and beta ranges, with modest effects during rule maintenance. Modafinil treatment in schizophrenia augments middle-frequency cortical oscillatory power associated with rule selection, and may subserve diverse subcomponent processes in proactive cognitive control.
PMCID: PMC4229573  PMID: 24964814
3.  Pupil diameter reflects uncertainty in attentional selection during visual search 
Pupil diameter has long been used as a metric of cognitive processing. However, recent advances suggest that the cognitive sources of change in pupil size may reflect LC-NE function and the calculation of unexpected uncertainty in decision processes (Aston-Jones and Cohen, 2005; Yu and Dayan, 2005). In the current experiments, we explored the role of uncertainty in attentional selection on task-evoked changes in pupil diameter during visual search. We found that task-evoked changes in pupil diameter were related to uncertainty during attentional selection as measured by reaction time (RT) and performance accuracy (Experiments 1-2). Control analyses demonstrated that the results are unlikely to be due to error monitoring or response uncertainty. Our results suggest that pupil diameter can be used as an implicit metric of uncertainty in ongoing attentional selection requiring effortful control processes.
PMCID: PMC4523788  PMID: 26300759
pupillometry; visual search; cognitive control; attentional selection; LC-NE system; uncertainty
4.  Impaired prefrontostriatonigral functional connectivity and substantia nigra hyperactivity in schizophrenia 
Biological psychiatry  2013;74(2):122-129.
The theory that prefrontal cortex (PFC) dysfunction in schizophrenia leads to excess subcortical dopamine (DA) has generated widespread interest because it provides a parsimonious account for two core features of schizophrenia, cognitive deficits and psychosis, respectively. However, there has been limited empirical validation of this model. Moreover, the identity of the specific subcortical brain regions and circuits that may be impaired as a result of PFC dysfunction and mediate its link to psychosis in schizophrenia remains unclear. We undertook this event-related fMRI study to test the hypothesis that PFC dysfunction is associated with altered function of and connectivity with DA regulating regions of the basal ganglia.
18 individuals with schizophrenia or schizoaffective disorder and 19 healthy control participants completed event-related fMRI during working memory. We conducted between-group contrasts of task-evoked, univariate, activation maps to identify regions of altered function in schizophrenia. We also compared the groups on the level of functional connectivity between a priori identified PFC and basal ganglia regions to determine if prefrontal disconnectivity in patients was present.
We observed task-evoked hyperactivity of the substantia nigra that occurred in association with prefrontal and striatal hypoactivity in the schizophrenia group. The magnitude of prefrontal functional connectivity with these dysfunctional basal ganglia regions was decreased in the schizophrenia group. Additionally, the level of nigrostriatal functional connectivity predicted the level of psychosis.
These results suggest that functional impairments of the prefrontostriatonigral circuit may be a common pathway linking the pathogenesis of cognitive deficits and psychosis in schizophrenia.
PMCID: PMC3620727  PMID: 23290498
schizophrenia; psychosis; fMRI; substantia nigra; prefrontal cortex; basal ganglia
5.  Prefrontal Cortical Deficits and Impaired Cognition-Emotion Interactions in Schizophrenia 
The American journal of psychiatry  2011;168(3):276-285.
Despite schizophrenia patients’ reports of diminished experience of emotion in interviews and self-report measures, their emotional experience in the presence of emotional stimuli and in daily life (“in the moment”) appears largely intact. To examine emotion-cognition interactions, the authors tested the hypothesis that schizophrenia patients have unimpaired in-the-moment emotional reactivity but have a deficit in prefrontal cortical mechanisms needed to maintain and report on experience following exposure to emotional stimuli.
Using a slow event-related functional MRI paradigm, the authors examined the brain activity of 23 schizophrenia patients and 24 healthy comparison subjects during trials in which they viewed an affective picture and, after a delay, reported their emotional experience while viewing it.
The patients’ self-reports of emotional experience differed from those of the healthy subjects when they rated their experience on dimensions inconsistent with the stimulus valence but not when the dimension was consistent with it. In the presence of emotional stimuli, brain activity in the patients was similar to that of the comparison subjects. During the delay, however, patients showed decreased activation in a network of brain structures, including the dorsolateral prefrontal cortex and other prefrontal, limbic, and paralimbic areas. In patients, the delay-related response of the dorsolateral prefrontal cortex to pleasant stimuli correlated negatively with an anhedonia measure.
These results suggest that schizophrenia is characterized by a failure of prefrontal circuitry supporting the link between emotion and goal-directed behavior and that the failure of this mechanism may contribute to deficits in processes related to emotion-cognition interaction.
PMCID: PMC4019338  PMID: 21205806
6.  Association of Dorsolateral Prefrontal Cortex Dysfunction With Disrupted Coordinated Brain Activity in Schizophrenia: Relationship With Impaired Cognition, Behavioral Disorganization, and Global Function 
The American journal of psychiatry  2008;165(8):1006-1014.
Although deficits in cognitive control are thought to contribute to the diverse cognitive and behavioral abnormalities in individuals with schizophrenia, the neural mechanisms underlying these deficits remain unclear. In this event-related functional magnetic resonance imaging (fMRI) study, the authors tested the hypothesis that during cognitive control tasks, impaired activation of the dorsolateral prefrontal cortex in schizophrenia patients is associated with disrupted coordinated activity between this prefrontal region and a distributed brain network that supports cognitive control.
Through the use of an event-related design, 25 patients with first-episode schizophrenia and 24 healthy comparison subjects, matched on demographic characteristics, were assessed while performing a version of the AX continuous performance task. Functional neuroimaging data were analyzed using 1) univariate (region-of-interest blood-oxygen-level-dependent [BOLD] time series and whole brain voxel-wise regression) analysis to confirm the presence of dorsolateral prefrontal cortex dysfunction and 2) multivariate analysis to examine dorsolateral prefrontal cortex functional connectivity. In addition, correlations between dorsolateral prefrontal cortex functional connectivity and the following variables were investigated: clinical symptoms, task performance, and coordinated brain activity associated with cognitive control.
Schizophrenia patients exhibited a specific deficit in cognitive control, with significantly reduced accuracy in the BX condition relative to any other condition. Univariate fMRI revealed dorsolateral prefrontal cortex dysfunction during the high cognitive control condition. Multivariate analysis revealed significant impairment in functional connectivity between the dorsolateral prefrontal cortex and task-relevant brain regions. Significant correlations were also found between dorsolateral prefrontal cortex functional connectivity and cognitive performance, behavioral disorganization, and global functioning.
These findings suggest that there is an association between decreased dorsolateral prefrontal cortex activity and connectivity and a task-related neural network. This deficit in coordinated brain activity may result in the disabling disorganization symptoms related to impaired cognition in individuals with schizophrenia.
PMCID: PMC3985422  PMID: 18519527
7.  Meta-analysis of 41 Functional Neuroimaging Studies of Executive Function in Schizophrenia 
Archives of general psychiatry  2009;66(8):811-822.
Prefrontal cortical dysfunction is frequently reported in schizophrenia. It remains unclear whether this represents the coincidence of several prefrontal region- and process-specific impairments or a more unitary dysfunction in a superordinate cognitive control network. Whether these impairments are properly considered reflective of hypofrontality vs hyperfrontality remains unresolved.
To test whether common nodes of the cognitive control network exhibit altered activity across functional neuroimaging studies of executive cognition in schizophrenia and to evaluate the direction of these effects.
Data Sources:
PubMed database.
Study Selection:
Forty-one English-language, peer-reviewed articles published prior to February 2007 were included. All reports used functional neuroimaging during executive function performance by adult patients with schizophrenia and reported whole-brain analyses in standard stereotactic space. Tasks primarily included the delayed match-to-sample, N-back, AX-CPT, and Stroop tasks.
Data Extraction:
Activation likelihood estimation modeling reported activation maxima as the center of a 3-dimensional gaussian function in the meta-analysis, with statistical thresholding and correction for multiple comparisons.
Data Synthesis:
In within-group analyses, healthy controls and patients activated a similarly distributed cortical-subcortical network, prominently including the dorsolateral prefrontal cortex (PFC), ventrolateral PFC, anterior cingulate cortex (ACC), and thalamus. In between-group analyses, patients showed reduced activation in the left dorsolateral PFC, rostral/dorsal ACC, left thalamus (with significant co-occurrence of these areas), and inferior/ posterior cortical areas. Increased activation was observed in several midline cortical areas. Activation within groups varied modestly by task.
Healthy adults and schizophrenic patients activate a qualitatively similar neural network during executive task performance, consistent with the engagement of a general-purpose cognitive control network, with critical nodes in the dorsolateral PFC and ACC. Nevertheless, patients with schizophrenia show altered activity with deficits in the dorsolateral PFC, ACC, and mediodorsal nucleus of the thalamus. Increases in activity are evident in other PFC areas, which could be compensatory in nature.
PMCID: PMC2888482  PMID: 19652121
8.  Pharmacotherapy for Attention-Deficit/Hyperactivity Disorder: From Cells to Circuits 
Neurotherapeutics  2012;9(3):610-621.
Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent disorder of childhood and adulthood, with a considerable impact on public health. There is a substantial pharmacopoeia available for safe and effective treatment of ADHD, and newly available agents diversify the treatment options. With the burgeoning scientific literature addressing the genetic, neurochemical, and neural systems basis for this condition, increasing attention is directed at establishing the neural basis for the efficacy of existing treatments. ADHD remains the only highly prevalent, nondegenerative neuropsychiatric disorder for which effective medications remediate the principal cognitive disturbances in concert with clinical efficacy. Therefore, deeper insight into the neural mechanisms of cognitive remediation may serve to advance treatment development not only in ADHD, but across a wide range of neuropsychiatric disorders in which cognitive dysfunction is a cardinal feature and a strong predictor of clinical outcome. To date, all effective medications for ADHD act on 1 or both of the major catecholamine neurotransmitter systems in the brain. These 2 systems, which arise from subcortical nuclei and use norepinephrine (NE) or dopamine (DA) as transmitters, exert strong modulatory effects on widely distributed cortical–subcortical neural circuits, with important effects on cognition, mood, and behavior, in both health and illness. The present review outlines the actions of ADHD medications from subcellular effects to effects on neural systems and cognition in ADHD patients. This is a very active area of investigation at all phases of the translational cycle, and near-term work is poised to firmly link cellular neuropharmacology to large-scale effects, and point the way toward advances in treatment.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-012-0128-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3441935  PMID: 22718077
Attention-deficit/hyperactivity disorder; Psychostimulants; Neuropharmacology; Norepinephrine; Dopamine; Cognition
9.  Proactive and reactive cognitive control and dorsolateral prefrontal cortex dysfunction in first episode schizophrenia☆ 
NeuroImage : Clinical  2013;2:590-599.
Cognitive control deficits have been consistently documented in patients with schizophrenia. Recent work in cognitive neuroscience has hypothesized a distinction between two theoretically separable modes of cognitive control—reactive and proactive. However, it remains unclear the extent to which these processes are uniquely associated with dysfunctional neural recruitment in individuals with schizophrenia. This functional magnetic resonance imaging (fMRI) study utilized the color word Stroop task and AX Continuous Performance Task (AX-CPT) to tap reactive and proactive control processes, respectively, in a sample of 54 healthy controls and 43 patients with first episode schizophrenia. Healthy controls demonstrated robust dorsolateral prefrontal, anterior cingulate, and parietal cortex activity on both tasks. In contrast, patients with schizophrenia did not show any significant activation during proactive control, while showing activation similar to control subjects during reactive control. Critically, an interaction analysis showed that the degree to which prefrontal activity was reduced in patients versus controls depended on the type of control process engaged. Controls showed increased dorsolateral prefrontal cortex (DLPFC) and parietal activity in the proactive compared to the reactive control task, whereas patients with schizophrenia did not demonstrate this increase. Additionally, patients' DLPFC activity and performance during proactive control was associated with disorganization symptoms, while no reactive control measures showed this association. Proactive control processes and concomitant dysfunctional recruitment of DLPFC represent robust features of schizophrenia that are also directly associated with symptoms of disorganization.
•Cognitive control and fronto-parietal recruitment are disrupted in schizophrenia.•Schizophrenia patients show hypoactivation during proactive not reactive control.•DLPFC activity was associated with disorganization only in proactive control.•Proactive control deficits may reflect a more robust marker of disease pathology.
PMCID: PMC3777717  PMID: 24179809
Cognitive control; Schizophrenia; DLPFC; Stroop; AX-CPT; fMRI
10.  Automated classification of fMRI during cognitive control identifies more severely disorganized subjects with schizophrenia 
Schizophrenia Research  2012;135(1-3):28-33.
The establishment of a neurobiologically based nosological system is one of the ultimate goals of modern biological psychiatry research. Developments in neuroimaging and statistical/machine learning have provided useful basic tools for these efforts. Recent studies have demonstrated the utility of fMRI as input data for the classification of schizophrenia, but none, to date, has used fMRI of cognitive control for this purpose. In this study, we evaluated the accuracy of an unbiased classification method on fMRI data from a large cohort of subjects with first episode schizophrenia and a cohort of age matched healthy control subjects while they completed the AX version of the Continuous Performance Task (AX-CPT). We compared these results to classifications based on AX-CPT behavioral data. Classification accuracy for DSM-IV defined schizophrenia using fMRI data was modest and comparable to classifications conducted with behavioral data. Interestingly fMRI classifications did however identify a distinct subgroup of patients with greater behavioral disorganization, whereas behavioral data classifications did not. These results suggest that fMRI-based classification could be a useful tool in defining a neurobiologically distinct subgroup within the clinically defined syndrome of schizophrenia, reflecting alterations in discrete neural circuits. Independent validation of classification-based phenotypes using other biological data such as genetics would provide a strong test of this hypothesis.
PMCID: PMC3288252  PMID: 22277668
Schizophrenia; fMRI; automated classification; nosology
11.  Involvement of the anterior cingulate and frontoinsular cortices in rapid processing of salient facial emotional information 
NeuroImage  2010;54(3):2539-2546.
The anterior cingulate cortex (ACC) and frontoinsular cortex (FI) have been implicated in processing information across a variety of domains, including those related to attention and emotion. However, their role in rapid information processing, for example, as required for timely processing of salient stimuli, is not well understood. Here, we designed an emotional face priming paradigm and employed functional magnetic resonance imaging to elucidate their role in these mechanisms. Target faces with either neutral or fearful emotion were briefly primed by either neutral or fearful faces, or by blank ovals. Activation in the pregenual ACC and the FI, together with other regions, such as the amygdala, were preferentially activated in response to fearful face priming, suggesting that these regions are involved in the rapid processing of salient facial emotional information.
PMCID: PMC3006498  PMID: 20937394
anterior cingulate cortex; emotion; fMRI; frontoinsular cortex; priming
12.  Cognitive Control Deficits in Schizophrenia: Mechanisms and Meaning 
Neuropsychopharmacology  2010;36(1):316-338.
Although schizophrenia is an illness that has been historically characterized by the presence of positive symptomatology, decades of research highlight the importance of cognitive deficits in this disorder. This review proposes that the theoretical model of cognitive control, which is based on contemporary cognitive neuroscience, provides a unifying theory for the cognitive and neural abnormalities underlying higher cognitive dysfunction in schizophrenia. To support this model, we outline converging evidence from multiple modalities (eg, structural and functional neuroimaging, pharmacological data, and animal models) and samples (eg, clinical high risk, genetic high risk, first episode, and chronic subjects) to emphasize how dysfunction in cognitive control mechanisms supported by the prefrontal cortex contribute to the pathophysiology of higher cognitive deficits in schizophrenia. Our model provides a theoretical link between cellular abnormalities (eg, reductions in dentritic spines, interneuronal dysfunction), functional disturbances in local circuit function (eg, gamma abnormalities), altered inter-regional cortical connectivity, a range of higher cognitive deficits, and symptom presentation (eg, disorganization) in the disorder. Finally, we discuss recent advances in the neuropharmacology of cognition and how they can inform a targeted approach to the development of effective therapies for this disabling aspect of schizophrenia.
PMCID: PMC3052853  PMID: 20844478
cognitive control; schizophrenia; cognition; disorganization; prefrontal cortex; executive functioning; schizophrenia/antipsychotics; cognition; imaging, clinical, or preclinical; neurophysiology; cognitive control; anterior cingulated; prefrontal cortex; high risk; DLPFC
13.  Gamma Oscillatory Power is Impaired During Cognitive Control Independent of Medication Status in First-Episode Schizophrenia 
Neuropsychopharmacology  2010;35(13):2590-2599.
Schizophrenia is characterized by impaired cognitive control associated with prefrontal cortex dysfunction, but the underlying pathophysioloical mechanisms remain unknown. Higher cognitive processes are associated with cortical oscillations in the gamma range, which are also impaired in chronic schizophrenia. We tested whether cognitive control-related gamma deficits are observed in first-episode patients, and whether they are associated with antipsychotic medication exposure. Fifty-three first-episode schizophrenia patients (21 without antipsychotic medication treatment) and 29 healthy control subjects underwent electroencephalography (EEG) during performance of a preparatory cognitive control task (preparing to overcome prepotency or POP task). The first-episode schizophrenia patient group was impaired (relative to the control group) on task performance and on delay-period gamma power at each of the three subgroups of frontal electrodes. The unmedicated patient subgroup was similarly impaired compared with controls, and was not different on these measures compared with the medicated patient subgroup. In contrast, delay-period theta power was not impaired in the full patient group nor in the unmedicated patient subgroup. Impaired cognitive control-related gamma cortical oscillatory activity is present at the first psychotic episode in schizophrenia, and is independent of medication status. This suggests that altered local circuit function supporting high-frequency oscillatory activity in prefrontal cortex ensembles may serve as the pathophysiological substrate of cognitive control deficits in schizophrenia.
PMCID: PMC3055567  PMID: 20827271
schizophrenia; gamma oscillations; cognitive control; first episode; prefrontal cortex; psychiatry & behavioral sciences; cognition; schizophrenia / antipsychotics; neurophysiology; schizophrenia; gamma oscillations; prefrontal cortex; cognitive contro; first-episode
14.  Cognitive Control Deficits in Schizophrenia: Mechanisms and Meaning 
Although schizophrenia is an illness that has been historically characterized by the presence of positive symptomatology, decades of research highlight the importance of cognitive deficits in this disorder. This review proposes that the theoretical model of cognitive control, which is based on contemporary cognitive neuroscience, provides a unifying theory for the cognitive and neural abnormalities underlying higher cognitive dysfunction in schizophrenia. To support this model, we outline converging evidence from multiple modalities (eg, structural and functional neuroimaging, pharmacological data, and animal models) and samples (eg, clinical high risk, genetic high risk, first episode, and chronic subjects) to emphasize how dysfunction in cognitive control mechanisms supported by the prefrontal cortex contribute to the pathophysiology of higher cognitive deficits in schizophrenia. Our model provides a theoretical link between cellular abnormalities (eg, reductions in dentritic spines, interneuronal dysfunction), functional disturbances in local circuit function (eg, gamma abnormalities), altered inter-regional cortical connectivity, a range of higher cognitive deficits, and symptom presentation (eg, disorganization) in the disorder. Finally, we discuss recent advances in the neuropharmacology of cognition and how they can inform a targeted approach to the development of effective therapies for this disabling aspect of schizophrenia.
PMCID: PMC3052853  PMID: 20844478
cognitive control; schizophrenia; cognition; disorganization; prefrontal cortex; executive functioning
15.  Broader Visual Orientation Tuning in Patients with Schizophrenia 
Reduced gamma-aminobutyric acid (GABA) levels in cerebral cortex are thought to contribute to information processing deficits in patients with schizophrenia (SZ), and we have previously reported lower in vivo GABA levels in the visual cortex of patients with SZ. GABA-mediated inhibition plays a role in sharpening orientation tuning of visual cortical neurons. Therefore, we predicted that tuning for visual stimulus orientation would be wider in SZ. We measured orientation tuning with a psychophysical procedure in which subjects performed a target detection task of a low-contrast oriented grating, following adaptation to a high-contrast grating. Contrast detection thresholds were determined for a range of adapter–target orientation offsets. For both SZ and healthy controls, contrast thresholds decreased as orientation offset increased, suggesting that this tuning curve reflects the selectivity of visual cortical neurons for stimulus orientation. After accounting for generalized deficits in task performance in SZ, there was no difference between patients and controls for detection of target stimuli having either the same orientation as the adapter or orientations far from the adapter. However, patients’ thresholds were significantly higher for intermediate adapter–target offsets. In addition, the mean width parameter of a Gaussian fit to the psychophysical orientation tuning curves was significantly larger for the patient group. We also present preliminary data relating visual cortical GABA levels, as measured with magnetic resonance spectroscopy, and orientation tuning width. These results suggest that our finding of broader orientation tuning in SZ may be due to diminished visual cortical GABA levels.
PMCID: PMC3208208  PMID: 22069385
schizophrenia; visual perception; GABA; MRS; psychophysics; tuning
16.  Modafinil modulation of the default mode network 
Psychopharmacology  2010;215(1):23-31.
The default mode network (DMN) is a functional network which is implicated in a range of cognitive processes. This network is proposed to consist of hubs located in the ventromedial prefrontal cortex (vmPFC), posterior cingulate/retrosplenial cortex (PCC/rSpl), and inferior parietal lobule (IPL), with other midline cortical and temporal lobe nodes connected to these hubs. How this network is modulated by neurochemical systems during functional brain activity is not yet understood.
In the present study, we used the norepinephrine/dopamine transporter inhibitor modafinil to test the hypothesis that this drug modulates the DMN.
Eighteen healthy right-handed adults participated in a double-blind, placebo-controlled study of single oral dose modafinil 200 mg. They performed a simple visual sensorimotor task during slow event-related fMRI. Drug effects were interrogated within the DMN defined by task-induced deactivation (TID) on placebo.
There was a trend toward faster reaction time (RT) on modafinil (Cohen’s d = 0.38). Brain regions within the DMN which exhibited significant modafinil-induced augmentation of TID included vmPFC, PCC/rSpl, and left IPL. Across subjects, the modafinil effect on TID in the vmPFC was significantly and specifically associated with drug effects on RT speeding.
Modafinil augments TID in the DMN to facilitate sensorimotor processing speed, an effect which may be particularly dependent on changes in vmPFC activity. This is consistent with the gain control function of catecholamine systems and may represent an important aspect of the pro-cognitive effects of modafinil.
Electronic supplementary material
The online version of this article (doi:10.1007/s00213-010-2111-5) contains supplementary material, which is available to authorized users.
PMCID: PMC3072511  PMID: 21153806
Catecholamines; Default mode network; Modafinil; Task-induced deactivation; Gain control; Negative BOLD response
17.  Diminished Orientation-Specific Surround Suppression of Visual Processing in Schizophrenia 
Schizophrenia Bulletin  2009;35(6):1078-1084.
Visual perception of a stimulus is a function of the visual context in which it is displayed. Surround suppression is a specific form of contextual modulation whereby the perceived contrast of a center stimulus is decreased by a high-contrast surround. Recent studies have demonstrated that individuals with schizophrenia are less prone to visual contextual effects, suggesting impairments in cortical lateral connectivity. We tested whether altered contextual modulation in schizophrenia is stimulus orientation selective. Participants viewed an annulus consisting of contrast-reversing sinusoidal gratings and determined if any one segment of the annulus had lower contrast relative to the other segments. Three stimulus configurations were tested: no surround (NS), parallel surround (PS), and orthogonal surround (OS). In the PS condition, the annulus was embedded in a 100% contrast grating parallel to the annulus gratings. In the OS condition, the surround grating was rotated 90° relative to the orientation of the annulus gratings. The main dependent measure was the suppression index—the change in contrast threshold in the OS and PS conditions relative to the NS condition. There was a group × condition interaction such that patients had significantly lower PS suppression index than controls, but there were no group differences in the OS suppression index. We conclude that individuals with schizophrenia possess an abnormality in surround suppression that is specific for stimulus orientation. In conjunction with physiological and anatomical evidence from basic and postmortem studies, our results suggest a deficit of inhibition in primary visual cortex in schizophrenia.
PMCID: PMC2762622  PMID: 19620601
schizophrenia; psychophysics; visual processing; contextual modulation
18.  Gamma-Aminobutyric Acid Concentration is Reduced in Visual Cortex in Schizophrenia and Correlates with Orientation-Specific Surround Suppression 
The neural mechanisms underlying cognitive deficits in schizophrenia remain largely unknown. The gamma-aminobutyric acid (GABA) hypothesis proposes that reduced neuronal GABA concentration and neurotransmission results in cognitive impairments in schizophrenia. However, few in vivo studies have directly examined this hypothesis. We employed magnetic resonance spectroscopy (MRS) at high field to measure visual cortical GABA levels in 13 subjects with schizophrenia and 13 demographically matched healthy control subjects. We found that the schizophrenia group had an approximately 10% reduction in GABA concentration. We further tested the GABA hypothesis by examining the relationship between visual cortical GABA levels and orientation-specific surround suppression (OSSS), a behavioral measure of visual inhibition thought to be dependent on GABAergic synaptic transmission. Previous work has shown that subjects with schizophrenia exhibit reduced OSSS of contrast discrimination (Yoon et al., 2009). For subjects with both MRS and OSSS data (n=16), we found a highly significant positive correlation (r=0.76) between these variables. GABA concentration was not correlated with overall contrast discrimination performance for stimuli without a surround (r=-0.10). These results suggest that a neocortical GABA deficit in subjects with schizophrenia leads to impaired cortical inhibition and that GABAergic synaptic transmission in visual cortex plays a critical role in OSSS.
PMCID: PMC2846788  PMID: 20220012
surround suppression; inhibition; schizophrenia; GABA; visual processing; cognitive deficits
19.  Multivariate pattern analysis of fMRI data reveals deficits in distributed representations in schizophrenia 
Biological psychiatry  2008;64(12):1035-1041.
Multivariate pattern analysis is an alternative method of analyzing fMRI data, which is capable of decoding distributed neural representations. We applied this method to test the hypothesis of the impairment in distributed representations in schizophrenia. We also compared the results of this method with traditional GLM-based univariate analysis.
19 schizophrenia and 15 control subjects viewed two runs of stimuli--exemplars of faces, scenes, objects, and scrambled images. To verify engagement with stimuli, subjects completed a 1-back matching task. A multi-voxel pattern classifier was trained to identify category-specific activity patterns on one run of fMRI data. Classification testing was conducted on the remaining run. Correlation of voxel-wise activity across runs evaluated variance over time in activity patterns.
Patients performed the task less accurately. This group difference was reflected in the pattern analysis results with diminished classification accuracy in patients compared to controls, 59% and 72% respectively. In contrast, there was no group difference in GLM-based univariate measures. In both groups, classification accuracy was significantly correlated with behavioral measures. Both groups showed highly significant correlation between inter-run correlations and classification accuracy.
Distributed representations of visual objects are impaired in schizophrenia. This impairment is correlated with diminished task performance, suggesting that decreased integrity of cortical activity patterns is reflected in impaired behavior. Comparisons with univariate results suggest greater sensitivity of pattern analysis in detecting group differences in neural activity and reduced likelihood of non-specific factors driving these results.
PMCID: PMC2772995  PMID: 18822407
schizophrenia; fMRI; visual processing; distributed representation; visual association cortex; multivariate pattern analysis
20.  Frontolimbic structural changes in borderline personality disorder 
Journal of psychiatric research  2007;42(9):727-733.
Frontolimbic dysfunction is observed in borderline personality disorder (BPD), with responses to emotional stimuli that are exaggerated in the amygdala and impaired in the anterior cingulate cortex (ACC). This pattern of altered function is consistent with animal models of stress responses and depression, where hypertrophic changes in the amygdala and atrophic changes in the ACC are observed. We tested the hypothesis that BPD patients exhibit gross structural changes that parallel the respective increases in amygdala activation and impairment of rostral/subgenual ACC activation.
12 unmedicated outpatients with BPD by DSM-IV and 12 normal control (NC) subjects underwent a high-resolution T1-weighted structural MRI scan. Relative gray matter concentration (GMC) in spatially-normalized images was evaluated by standard voxel-based morphometry, with voxel-wise subject group comparisons by t test constrained to amygdala and rostral/subgenual ACC.
The BPD group was significantly higher than NC in GMC in the amygdala. In contrast, the BPD group showed significantly lower GMC than the NC group in left rostral/subgenual ACC.
This sample of BPD patients exhibits gross structural changes in gray matter in cortical and subcortical limbic regions that parallel the regional distribution of altered functional activation to emotional stimuli among these same subjects. While the histological basis for GMC changes in adult clinical populations is poorly-known at present, the observed pattern is consistent with the direction of change, in animal models of anxiety and depression, of neuronal number and/or morphological complexity in both the amygdala (where it is increased) and ACC (where it is decreased).
PMCID: PMC2708084  PMID: 17825840
borderline personality disorder; frontolimbic; amygdala; anterior cingulate cortex; gray matter; voxel-based morphometry
21.  Frontolimbic dysfunction in response to facial emotion in borderline personality disorder: an event-related fMRI study 
Psychiatry research  2007;155(3):231-243.
Clinical hallmarks of borderline personality disorder (BPD) include social and emotional dysregulation. We tested a model of frontolimbic dysfunction in facial emotion processing in BPD. Groups of 12 unmedicated adults with BPD by DSM-IV and 12 demographically-matched healthy controls (HC) viewed facial expressions (Conditions) of neutral emotion, fear and anger, and made gender discriminations during rapid event-related functional magnetic resonance imaging (fMRI). Analysis of variance of Region of Interest signal change revealed a statistically significant effect of the Group-by-Region-by-Condition interaction. This was due to the BPD group exhibiting a significantly larger magnitude of deactivation (relative to HC) in the bilateral rostral/subgenual anterior cingulate cortex (ACC) to fear and in the left ACC to fear minus neutral; and significantly greater activation in the right amygdala to fear minus neutral. There were no significant between-group differences in ROI signal change in response to anger. In voxel-wise analyses constrained within these ROIs, the BPD group exhibited significant changes in the fear minus neutral contrast, with relatively less activation in the bilateral rostral/subgenual ACC, and greater activation in the right amygdala. In the anger minus neutral contrast this pattern was reversed, with the BPD group showing greater activation in the bilateral rostral/subgenual ACC and less activation in the bilateral amygdala. We conclude that adults with BPD exhibit changes in fronto-limbic activity in the processing of fear stimuli, with exaggerated amygdala response and impaired emotion-modulation of ACC activity. The neural substrates underlying processing of anger may also be altered. These changes may represent an expression of the volumetric and serotonergic deficits observed in these brain areas in BPD.
PMCID: PMC2084368  PMID: 17601709
anterior cingulate cortex; amygdala; fear; anger; functional magnetic resonance imaging

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