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Background Major Depressive Disorder (MDD) is commonly accompanied by cognitive control dysfunction that may persist after remission of clinical symptoms with antidepressant medication treatment. Repetitive Transcranial Magnetic Stimulation (rTMS) is an effective treatment alternative for medication-resistant MDD. In this study, we investigated whether rTMS treatment had a beneficial effect not only on depressive symptoms, but on also cognitive control dysfunction. Methods 77 subjects with MDD received a 30-session treatment course of 10 Hz rTMS administered at the left dorsolateral prefrontal cortex (DLPFC). Treatment efficacy was assessed using the Inventory of Depressive Symptomatology Self-Rated (IDS-SR) before and after treatment, with clinical response defined as 50% or greater decrease in the IDS-SR score at treatment 30. Cognitive control function was assessed before and after treatment using the Stroop word-color interference task. We examined changes in Stroop accuracy and reaction time for congruent and incongruent trials, as well as in relation to changes in depressive symptoms. Results Performance accuracy improved particularly for the rTMS responders in the incongruent condition, with older subjects benefitting most from the rTMS treatment. Improvement in reaction times was positively associated with clinical improvement, especially in the incongruent condition. Limitations We used a single cognitive task in a naturalistic setting without control for individual rTMS treatment parameters or concomitant medication. Conclusions Overall, these results indicate that rTMS treatment for MDD has beneficial effects on psychomotor speed and cognitive control. Future studies should extend these findings to larger patient populations and other cognitive domains.

Author(s): Levitt, Jennifer G; Kalender, Guldamla; O’Neill, Joseph; Diaz, Joel P; Cook, Ian A; Ginder, Nathaniel; Krantz, David; Minzenberg, Michael J; Vince-Cruz, Nikita; Nguyen, Lydia D; Alger, Jeffry R; Leuchter, Andrew F | Abstract: BackgroundThe therapeutic mechanism of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression (TRD) may involve modulation of γ-aminobutyric acid (GABA) levels. We used proton magnetic resonance spectroscopy (MRS) to assess changes in GABA levels at the site of rTMS in the left dorsolateral prefrontal cortex (DLPFC).MethodsIn 26 adults with TRD, we used Mescher–Garwood point-resolved spectroscopy (MEGA-PRESS) spectral-editing MRS to measure GABA in the left DLPFC before and after standard clinical treatment with rTMS. All participants but 1 were medicated, including 12 patients on GABA agonist agents.ResultsMean GABA in the DLPFC increased 10.0% (p = 0.017) post-rTMS in the overall sample. As well, GABA increased significantly in rTMS responders (n = 12; 23.6%, p = 0.015) but not in nonresponders (n = 14; 4.1%, p = not significant). Changes in GABA were not significantly affected by GABAergic agonists, but clinical response was less frequent (p = 0.005) and weaker (p = 0.035) in the 12 participants who were receiving GABA agonists concomitant with rTMS treatment.LimitationsThis study had an open-label design in a population receiving naturalistic treatment.ConclusionTreatment using rTMS was associated with increases in GABA levels at the stimulation site in the left DLPFC, and the degree of GABA change was related to clinical improvement. Participants receiving concomitant treatment with a GABA agonist were less likely to respond to rTMS. These findings were consistent with earlier studies showing the effects of rTMS on GABA levels and support a GABAergic model of depression.

Objective Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for neuropsychiatric disorders. Patients in rTMS treatment typically receive concomitant psychotropic medications, which affect neuronal excitability and plasticity and may interact to affect rTMS treatment outcomes. A greater understanding of these drug effects may have considerable implications for optimizing multi-modal treatment of psychiatric patients, and elucidating the mechanism(s) of action (MOA) of rTMS. Method We summarized the empirical literature that tests how psychotropic drugs affect cortical excitability and plasticity, using varied experimental TMS paradigms. Results Glutamate antagonists robustly attenuate plasticity, largely without changes in excitability per se; antiepileptic drugs show the opposite pattern of effects, while calcium channel blockers attenuate plasticity. Benzodiazepines have moderate and variable effects on plasticity, and negligible effects on excitability. Antidepressants with potent 5HT transporter inhibition reduce both excitability and alter plasticity, while antidepressants with other MOAs generally lack either effect. Catecholaminergic drugs, cholinergic agents and lithium have minimal effects on excitability but exhibit robust and complex, non-linear effects in TMS plasticity paradigms. Limitations These effects remain largely untested in sustained treatment protocols, nor in clinical populations. In addition, how these medications impact clinical response to rTMS remains largely unknown. Conclusions Psychotropic medications exert robust and varied effects on cortical excitability and plasticity. We encourage the field to more directly and fully investigate clinical pharmaco-TMS studies to improve outcomes.

Repetitive transcranial magnetic stimulation (rTMS) treatment of major depressive disorder (MDD) is associated with changes in brain functional connectivity (FC). These changes may be related to the mechanism of action of rTMS and explain the variability in clinical outcome. We examined changes in electroencephalographic FC during the first rTMS treatment in 109 subjects treated with 10 Hz stimulation to left dorsolateral prefrontal cortex. All subjects subsequently received 30 treatments and clinical response was defined as ≥40% improvement in the inventory of depressive symptomatology-30 SR score at treatment 30. Connectivity change was assessed with coherence, envelope correlation, and a novel measure, alpha spectral correlation (αSC). Machine learning was used to develop predictive models of outcome for each connectivity measure, which were compared with prediction based upon early clinical improvement. Significant connectivity changes were associated with clinical outcome (P < 0.001). Machine learning models based on αSC yielded the most accurate prediction (area under the curve, AUC = 0.83), and performance improved when combined with early clinical improvement measures (AUC = 0.91). The initial rTMS treatment session produced robust changes in FC, which were significant predictors of clinical outcome of a full course of treatment for MDD.

Blunted and exaggerated neuronal response to rewards are hypothesized to be core features of schizophrenia spectrum disorders (SZ) and bipolar disorder (BD), respectively. Nonetheless, direct tests of this hypothesis, in which response between SZ and BD is compared in the same study, are lacking. Here we examined the functional correlates of reward processing during the Incentivized Control Engagement Task (ICE-T) using 3T fMRI. Reward-associated activation was examined in 49 healthy controls (HCs), 52 recent-onset individuals with SZ, and 22 recent-onset individuals with Type I BD using anterior cingulate (ACC), anterior insula, and ventral striatal regions of interest. Significant group X reward condition (neutral vs. reward) interactions were observed during reward anticipation in the dorsal ACC (F(2,120) = 4.21, P = 0.017) and right insula (F(2,120) = 4.77, P = 0.010). The ACC interaction was driven by relatively higher activation in the BD group vs. HCs (P = 0.007) and vs. individuals with SZ (P = 0.010). The insula interaction was driven by reduced activation in the SZ group relative to HCs (P = 0.018) and vs. people with BD (P = 0.008). A composite of reward anticipation-associated response across all associated ROIs also differed significantly by diagnosis (F(1,120) = 5.59, P = 0.02), BD > HC > SZ. No effects of group or group X reward interactions were observed during reward feedback. These results suggest that people with SZ and BD have opposite patterns of activation associated with reward anticipation but not reward receipt. Implications of these findings in regard to Research Domain Criteria-based classification of illness and the neurobiology of reward in psychosis are discussed.

Transcranial magnetic stimulation (TMS) is a safe and effective therapeutic modality for a rapidly expanding range of neuropsychiatric indications. Among psychiatric conditions, it is presently approved by the US Food and Drug Administration for treatment-resistant unipolar major depressive disorder and obsessive-compulsive disorder, 2 highly prevalent conditions with a considerable public health impact. There is also mounting evidence for its clinical utility in numerous other neuropsychiatric conditions. Nonetheless, many mental health providers, as well as primary care and other providers, remain unfamiliar with its clinical use. In this primer, we seek to describe in nontechnical terms how the magnetic field is applied to the brain, the unmet needs that may be remediated with TMS, the present state of evidence for clinical effectiveness, particularly in major depressive disorder, the safety profile of TMS, what patients experience during TMS, and some recent developments that serve to advance the use of this still novel intervention. TMS is poised to assume an important place in the armamentarium of interventions to better serve our patients, especially those with serious, chronic conditions with high rates of resistance to more conventional treatments. Consequently, it is essential that mental health providers gain as adequate a working knowledge of device-based interventions such as TMS as they currently have of psychopharmacological and psychosocial interventions. Among other potential benefits, this information should aid the process of obtaining informed consent from patients who are candidates for these treatments.

Repetitive transcranial magnetic stimulation (rTMS) has demonstrated efficacy in major depressive disorder (MDD), although clinical outcome is variable. Change in the resting-state quantitative electroencephalogram (qEEG), particularly in theta cordance early in the course of treatment, has been linked to antidepressant medication outcomes but has not been examined extensively in clinical rTMS. This study examined change in theta cordance over the first week of clinical rTMS and sought to identify a biomarker that would predict outcome at the end of 6 weeks of treatment. Clinically stable outpatients (n = 18) received nonblinded rTMS treatment administered to the dorsolateral prefrontal cortex (DLPFC). Treatment parameters (site, intensity, number of pulses) were adjusted on an ongoing basis guided by changes in symptom severity rating scale scores. qEEGs were recorded at pretreatment baseline and after 1 week of left DLPFC (L-DLPFC) rTMS using a 21-channel dry-electrode headset. Analyses examined the association between week 1 regional changes in theta band (4-8 Hz) cordance, and week 6 patient- and physician-rated outcomes. Theta cordance change in the central brain region predicted percent change in Inventory of Depressive Symptomology–Self-Report (IDS-SR) score, and improvement versus nonimprovement on the Clinical Global Impression–Improvement Inventory (CGI-I) ( R2 = .38, P = .007; and Nagelkerke R2 = .78, P = .0001, respectively). The cordance biomarker remained significant when controlling for age, gender, and baseline severity. Treatment-emergent change in EEG theta cordance in the first week of rTMS may predict acute (6-week) treatment outcome in MDD. This oscillatory synchrony biomarker merits further study in independent samples.

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for Major Depressive Disorder (MDD). There are clinical data that support the efficacy of many different approaches to rTMS treatment, and it remains unclear what combination of stimulation parameters is optimal to relieve depressive symptoms. Because of the costs and complexity of studies that would be necessary to explore and compare the large number of combinations of rTMS treatment parameters, it would be useful to establish reliable surrogate biomarkers of treatment efficacy that could be used to compare different approaches to treatment. This study reviews the evidence that neurophysiologic measures of cortical excitability could be used as biomarkers for screening different rTMS treatment paradigms. It examines evidence that: (1) changes in excitability are related to the mechanism of action of rTMS; (2) rTMS has consistent effects on measures of excitability that could constitute reliable biomarkers; and (3) changes in excitability are related to the outcomes of rTMS treatment of MDD. An increasing body of evidence indicates that these neurophysiologic measures have the potential to serve as reliable biomarkers for screening different approaches to rTMS treatment of MDD.

Working memory (WM) deficits are key features of schizophrenia and are associated with significant functional impairment. The precise mechanisms of WM and their relationship between WM deficits with other clinical symptoms of schizophrenia remain unclear. Contemporary models propose that WM requires synchronous activity across brain regions within a distributed network, including lateral prefrontal cortex (PFC) and task-relevant posterior sensory cortical regions. This suggests that WM deficits in patients may be due to PFC functional connectivity (FC) impairments rather than activation impairments per se. We tested this hypothesis by measuring the magnitude of FC between lateral PFC and visual cortex and univariate activations within these regions during visual WM. We found decreased FC in patients compared to healthy subjects in the context of similar levels of univariate activity. Furthermore, this decreased FC was associated with task performance and clinical symptomatology in patients. The magnitude of FC, particularly during the delay period, was positively correlated with WM task accuracy, while FC during cue was inversely correlated with severity of disorganization. Taken together, these results suggest that impairment in lateral PFC FC is a key aspect of information processing impairment in patients with schizophrenia, and may be a sensitive index of altered neurophysiology.

The GABA deficit hypothesis remains one of the most compelling explanations for the information processing impairments in schizophrenia. However, much of the supportive evidence has been derived from post-mortem studies, whereas in vivo studies have largely yielded inconsistent results. We undertook this single voxel proton magnetic resonance (MRS) GABA study to test in a sample of recent onset patients the replicability of our prior finding of reduced early visual cortex GABA in schizophrenia. We also examined the possibility that antipsychotics could represent a significant confound by studying a small subsample of antipsychotic naive subjects. 23 adults with recent onset schizophrenia and a demographically matched sample of 31 healthy control subjects underwent MRS using a MEGA PRESS sequence on a 3T MR scanner to measure GABA concentration in early visual cortex. To control for in-scanner head movement confounding the results, we quantified the amount of head movement during GABA scans to identify and exclude from analysis scans with excessive movement. Patients demonstrated significantly reduced GABA levels compared to control subjects, p = 0.029. GABA levels did not differ significantly between patients who were antipsychotic naive (n = 7) and patients treated with antipsychotics. This replication in a recent onset sample suggest that diminished GABA in the visual cortex is a reliable finding, present in early phase of illness and not confounded by illness chronicity.

Suicidal ideation and behavior are highly prevalent in psychotic major mood disorders, yet their relationship to brain function remains unclear. Thirty patients with recent-onset of bipolar disorder type I (N=21) or major depressive disorder (N=9) with past psychosis were evaluated for past suicidal ideation/behavior and functional MRI during conflict-monitoring. Suicidal ideation was related to relatively higher dorsal anterior cingulate cortex (dACC)-seeded functional connectivity with dorsal fronto-parietal and inferior temporal-occipital cortex, as well as lower dACC connectivity with bilateral ventrolateral prefrontal cortex (PFC) and adjacent fronto-striatal regions. Past suicidal behavior was associated with lower dACC functional connectivity with dorsolateral PFC and premotor cortex, as well as temporal-parietal cortex.

The subthalamic nucleus (STN) is thought to be a central regulator of behavioral inhibition, which is thought to be a major determinant of impulsivity. Thus, it would be reasonable to hypothesize that STN function is related to impulsivity. However, it has been difficult to test this hypothesis because of the challenges in noninvasively and accurately measuring this structure's signal in humans. We utilized a novel approach for STN signal localization that entails identifying this structure directly on fMRI images for each individual participant in native space. Using this approach, we measured STN responses during the stop signal task in a sample of healthy adult participants. We confirmed that the STN exhibited selective activation during “Stop” trials. Furthermore, the magnitude of STN activation during successful Stop trials inversely correlated with individual differences in trait impulsivity as measured by a personality inventory. Time course analysis revealed that early STN activation differentiated successful from unsuccessful Stop trials, and individual differences in the magnitude of STN activation inversely correlated with stop signal RT, an estimate of time required to stop. These results are consistent with the STN playing a central role in inhibition and related behavioral proclivities, with implications for both normal range function and clinical syndromes of inhibitory dyscontrol. Moreover, the methods utilized in this study for measuring STN fMRI signal in humans may be gainfully applied in future studies to further our understanding of the role of the STN in regulating behavior and neuropsychiatric conditions.

Candidate pro-cognitive drugs for schizophrenia targeting several neurochemical systems have consistently failed to demonstrate robust efficacy. It remains untested whether concurrent antipsychotic medications exert pharmacodynamic interactions that mitigate pro-cognitive action in patients. We used functional MRI (fMRI) in a randomized, double-blind, placebo-controlled within-subject crossover test of single-dose modafinil effects in 27 medicated schizophrenia patients, interrogating brainstem regions where catecholamine systems arise to innervate the cortex, to link cellular and systems-level models of cognitive control. Modafinil effects were evaluated both within this patient group and compared to a healthy subject group. Modafinil modulated activity in the locus coeruleus (LC) and ventral tegmental area (VTA) in the patient group. However, compared to the healthy comparison group, these effects were altered as a function of task demands: the control-independent drug effect on deactivation was relatively attenuated (shallower) in the LC and exaggerated (deeper) in the VTA; in contrast, again compared to the comparison group, the control-related drug effects on positive activation were attenuated in LC, VTA and the cortical cognitive control network. These altered effects in the LC and VTA were significantly and specifically associated with the degree of antagonism of alpha-2 adrenergic and dopamine-2 receptors, respectively, by concurrently prescribed antipsychotics. These sources of evidence suggest interacting effects on catecholamine neurons of chronic antipsychotic treatment, which respectively increase and decrease sustained neuronal activity in LC and VTA. This is the first direct evidence in a clinical population to suggest that antipsychotic medications alter catecholamine neuronal activity to mitigate pro-cognitive drug action on cortical circuits.

Repetitive transcranial magnetic stimulation (rTMS) treatment of major depressive disorder (MDD) is associated with changes in brain functional connectivity (FC). These changes may be related to the mechanism of action of rTMS and explain the variability in clinical outcome. We examined changes in electroencephalographic FC during the first rTMS treatment in 109 subjects treated with 10 Hz stimulation to left dorsolateral prefrontal cortex. All subjects subsequently received 30 treatments and clinical response was defined as ≥40% improvement in the inventory of depressive symptomatology-30 SR score at treatment 30. Connectivity change was assessed with coherence, envelope correlation, and a novel measure, alpha spectral correlation (αSC). Machine learning was used to develop predictive models of outcome for each connectivity measure, which were compared with prediction based upon early clinical improvement. Significant connectivity changes were associated with clinical outcome (P < 0.001). Machine learning models based on αSC yielded the most accurate prediction (area under the curve, AUC = 0.83), and performance improved when combined with early clinical improvement measures (AUC = 0.91). The initial rTMS treatment session produced robust changes in FC, which were significant predictors of clinical outcome of a full course of treatment for MDD.

Control-related cognitive processes such as rule selection and maintenance are associated with cortical oscillations in the gamma range, and modulated by catecholamine neurotransmission. Control-related gamma power is impaired in schizophrenia, and an understudied treatment target. It remains unknown whether pro-catecholamine pharmacological agents augment control-related gamma oscillations in schizophrenia. We tested the effects of 4-week fixed-dose daily adjunctive modafinil (MOD) 200 mg, in a randomized double-blind, placebo-controlled, parallel-groups design. Twenty-seven stable schizophrenia patients performed a cognitive control task during EEG, at baseline and after 4 weeks of treatment. EEG data underwent time-frequency decomposition with Morlet wavelets to determine power of 4-80 Hz oscillations. The modafinil group (n=14), relative to placebo group (n=13), exhibited enhanced oscillatory power associated with high-control rule selection in the gamma range after treatment, with additional effects during rule maintenance in gamma and sub-gamma ranges. MOD-treated patients who exhibited improved task performance with treatment also showed greater treatment-related delay period gamma compared with MOD-treated patients without improved performance. This is the first evidence in schizophrenia of augmentation of cognition-related gamma oscillations by an FDA-approved agent with therapeutic potential. Gamma oscillations represent a novel treatment target in this disorder, and modulation of catecholamine signaling may represent a viable strategy at this target.

Suicide is highly prevalent in schizophrenia (SZ), yet it remains unclear how suicide risk factors such as past suicidal ideation or behavior relate to brain function. Circuits modulated by the prefrontal cortex (PFC) are altered in SZ, including in dorsal anterior cingulate cortex (dACC) during conflict-monitoring (an important component of cognitive control), and dACC changes are observed in post-mortem studies of heterogeneous suicide victims. We tested whether conflict-related dACC functional connectivity is associated with past suicidal ideation and behavior in SZ. 32 patients with recent-onset of DSM-IV-TR-defined SZ were evaluated with the Columbia Suicide Severity Rating Scale and functional MRI during cognitive control (AX-CPT) task performance. Group-level regression models relating past history of suicidal ideation or behavior to dACC-seeded functional connectivity during conflict-monitoring controlled for severity of depression, psychosis and impulsivity. Past suicidal ideation was associated with relatively higher functional connectivity of the dACC with the precuneus during conflict-monitoring. Intensity of worst-point past suicidal ideation was associated with relatively higher dACC functional connectivity in medial parietal lobe and striato-thalamic nuclei. In contrast, among those with past suicidal ideation (n = 17), past suicidal behavior was associated with lower conflict-related dACC connectivity with multiple lateral and medial PFC regions, parietal and temporal cortical regions. This study provides unique evidence that recent-onset schizophrenia patients with past suicidal ideation or behavior show altered dACC-based circuit function during conflict-monitoring. Suicidal ideation and suicidal behavior have divergent patterns of associated dACC functional connectivity, suggesting a differing pattern of conflict-related brain dysfunction with these two distinct features of suicide phenomenology.

Author(s): Hunter, Aimee M; Minzenberg, Michael J; Cook, Ian A; Krantz, David E; Levitt, Jennifer G; Rotstein, Natalie M; Chawla, Shweta A; Leuchter, Andrew F | Abstract: BackgroundRepetitive Transcranial Magnetic Stimulation (rTMS) is commonly administered to Major Depressive Disorder (MDD) patients taking psychotropic medications, yet the effects on treatment outcomes remain unknown. We explored how concomitant medication use relates to clinical response to a standard course of rTMS.MethodsMedications were tabulated for 181 MDD patients who underwent a six-week rTMS treatment course. All patients received 10nHz rTMS administered to left dorsolateral prefrontal cortex (DLPFC), with 1nHz administered to right DLPFC in patients with inadequate response to and/or intolerance of left-sided stimulation. Primary outcomes were change in Inventory of Depressive Symptomatology Self Report (IDS-SR30) total score after 2, 4, and 6nweeks.ResultsUse of benzodiazepines was associated with less improvement at week 2, whereas use of psychostimulants was associated with greater improvement at week 2 and across 6nweeks. These effects were significant controlling for baseline variables including age, overall symptom severity, and severity of anxiety symptoms. Response rates at week 6 were lower in benzodiazepine users versus non-users (16.4% vs. 35.5%, pn=n0.008), and higher in psychostimulant users versus non-users (39.2% vs. 22.0%, pn=n0.02).ConclusionsConcomitant medication use may impact rTMS treatment outcome. While the differences reported here could be considered clinically significant, results were not corrected for multiple comparisons and findings should be replicated before clinicians incorporate the evidence into clinical practice. Prospective, hypothesis-based treatment studies will aid in determining causal relationships between medication treatments and outcome.

Control-related cognitive processes are associated with cortical oscillations and modulated by catecholamine neurotransmitters. It remains unclear how catecholamine systems modulate control-related oscillations. We tested modafinil effects on rule-related 4‐30 Hz oscillations, with double-blind, placebo-controlled (within-subjects) testing of 22 healthy adults, using EEG during cognitive control task performance. EEG data underwent time-frequency decomposition with Morlet wavelets to determine power of 4‐30 Hz oscillations. Modafinil enhanced oscillatory power associated with high-control rule selection in theta, alpha, and beta ranges, with a frontotemporal topography and minimal effects during rule maintenance.Augmentation of catecholamine signaling enhances middle-frequency cortical oscillatory power associated with rule selection, which may subserve diverse subcomponent processes in proactive cognitive control. Descriptors: Cognitive control, Rule selection, Oscillations, Modafinil, Prefrontal cortex, Theta

While structural abnormalities of the dorsolateral prefrontal cortex (DLPFC) may pre-date and predict psychosis onset, the relationships between functional deficits, cognitive and psychosocial impairments has yet to be explored in the at-risk period. An established measure of cognitive control (AXCPT) was administered to demographically matched clinical-high-risk (CHR; n=25), first-episode schizophrenia (FE; n=35), and healthy control (HC; n=35) participants during functional magnetic resonance imaging (fMRI) to investigate these relationships. CHR and FE individuals demonstrated impaired context processing and reduced DLPFC activation relative to HC individuals during increased cognitive control demands. FE and CHR individuals' ability to increase DLPFC activity in response to cognitive control demands was associated with better task performance. Task performance was also associated with severity of disorganization and poverty symptoms in FE participants. These findings support more extensive studies using fMRI to examine the clinical significance of prefrontal cortical functioning in the earliest stages of psychosis.

Schizophrenia patients experience cognitive control disturbances, manifest in altered neural signatures during action monitoring. It remains unclear whether error- and conflict-monitoring disturbances co-occur, and whether they are observed in recent-onset psychosis patients with schizophrenia or bipolar disorder. We tested electrophysiological measures of action monitoring in these patients. Seventy-three schizophrenia patients (SZ), 26 bipolar disorder type I patients (BP), each within one year of psychosis onset, and 54 healthy control subjects (HC) underwent EEG during Stroop task performance. In the trial-averaged EEG at three midline scalp electrodes, the error-related negativity (ERN), error positivity (Pe) and conflict-related N450 were measured. Compared to HC (1) SZ exhibited an attenuated ERN and N450, and Pe unchanged and (2) BP exhibited an attenuated ERN but normal Pe and N450. Between patient groups, SZ showed an attenuated N450; ERN and Pe were not significantly different. A small (n=10) SZ subgroup that was not receiving antipsychotic medication showed normal ERPs. Altered error- and conflict-monitoring occur together in the first-episode schizophrenia patients, and these measures are comparable in patients with the first-episode bipolar disorder. Antipsychotic medication may be associated with altered measures of error-monitoring in schizophrenia.

When predicting where a target or reward will be, participants tend to choose each location commensurate with the true underlying probability (i.e., probability match). The strategy of probability matching involves independent sampling of high and low probability locations on separate trials. In contrast, models of probabilistic spatial attention hypothesize that on any given trial attention will either be weighted toward the high probability location or be distributed equally across all locations. Thus, the strategies of probabilistic sampling by choice decisions and spatial attention appear to differ with regard to low-probability events. This distinction is somewhat surprising because similar brain mechanisms (e.g., pFC-mediated cognitive control) are thought to be important in both functions. Thus, the goal of the current study was to examine the relationship between choice decisions and attentional selection within single trials to test for any strategic differences, then to determine whether that relationship is malleable to manipulations of catecholamine-modulated cognitive control with the drug modafinil. Our results demonstrate that spatial attention and choice decisions followed different strategies of probabilistic information selection on placebo, but that modafinil brought the pattern of spatial attention into alignment with that of predictive choices. Modafinil also produced earlier learning of the probability distribution. Together, these results suggest that enhancing cognitive control mechanisms (e.g., through prefrontal cortical function) leads spatial attention to follow choice decisions in selecting information according to rule-based expectations.

Schizophrenia is characterized by significant problems in control of behavior; however, the disturbances in neural systems that control movement remain poorly characterized. We used functional magnetic resonance imaging (fMRI) to evaluate the origin of motor overflow in schizophrenia. Twenty-seven clinically stable medicated outpatients with Diagnostic and Statistical Manual, 4th edition, text revision (DSM-IV-TR)-defined schizophrenia (SZ), and 18 healthy control (HC) subjects, all right-handed, performed a dominant-handed, single-choice visual sensorimotor reaction time paradigm during fMRI. Voxel-wise analyses were conducted within sensorimotor cortical and striatal regions on general linear model (GLM)-derived measures of blood oxygen level-dependent (BOLD) signal change. The SZ group was not different from the HC group in reaction time, activation in somatosensory or motor cortices ipsilateral to the active (intended) descending corticospinal tract, nor visual cortex. However, in the right hemisphere (contralateral to the active M1), the SZ group showed significantly higher activation in primary motor cortex and adjacent premotor and somatosensory cortices (right Brodmann areas (BA) 1 through 4, and 6), and significantly lower activation in bilateral basal ganglia. Right BA 4 activation was strongly related to disorganization and poverty symptoms (and unrelated to medications) in the patient group. This study provides evidence in SZ of excessive neural activity in motor cortex contralateral to the intended primary motor cortex, which may form the basis for altered motor laterality and motor overflow previously observed, and disorganized behavior. This pathological motor overflow may be partly due to altered modulation of intended movement within the basal ganglia and premotor cortex.

Individuals with autism and schizophrenia exhibit atypical language and social symptoms. The extent to which these symptoms are evident during development and in current functioning is unclear.Three groups of patients aged 11-20 diagnosed as clinical-high-risk for psychosis (CHR; n=15), first episode psychosis (FEP; n=16), and autism spectrum disorders (ASD; n=20), plus typically developing individuals (TYP; n=20) were compared on common autism parent-report questionnaires assessing social and language development and current functioning including the Social Communication Questionnaire, the Children's Communication Checklist, and the Social Reciprocity Scale.All clinical groups demonstrated atypical social and language development, with social impairment highest in ASD. Twenty percent of participants with CHR and FEP met diagnostic criteria for ASD as assessed by parent-report. ASD exhibited greater current syntactic, and pragmatic language symptoms including delayed echolalia, pedantic speech, and deficits in appreciating irony and sarcasm. All clinical groups exhibited current deficits in social functioning. CHR and FE had similar and intermediate levels of functioning relative to ASD and TYP, with CHR generally scoring closer to TYP, providing construct validity for the CHR diagnostic label.The results of this study suggest that ASDs, CHR, and FEP share common features of atypical neurodevelopment of language and social function. Evidence of impaired social reciprocity across both disorders and distinct language symptoms in ASDs provides important information for differential diagnosis and psychosis prevention, as well as leads for future investigations of comparative genetics and pathophysiology.

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. 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. (C) 2010 Elsevier Inc. All rights reserved.

Antipsychotic medications exert variable and clinically significant levels of antagonism at central α-adrenergic receptors. To evaluate the impact of this activity on both clinical and experimental measures, an index estimating the relative activity of these medications is needed. We comprehensively searched the empirical literature testing in vitro binding to mammalian brain α-adrenergic receptors of all antipsychotic medications available for clinical use in the United States as of August 2010 and created a quantitative summary index of the potency of binding to α receptors relative to haloperidol (HALα1 and HALα2 equivalents). The potency of binding at α1- and α2-adrenergic receptors varies widely among these medications, with a 532-fold range for α1 antagonism and a 400-fold range for α2 antagonism among atypical antipsychotics. There is considerable overlap between atypical and typical antipsychotic medication groups on each of these measures. This index of HALα equivalents should facilitate the determination of the effects of α-adrenergic antagonism by these medications on clinical efficacy, side effects, and biological and cognitive measures of illness and treatment.

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.

Schizophrenia is characterized by impaired cognitive control associated with prefrontal cortex dysfunction, but the underlying pathophysiological 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.

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 degrees 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 x 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.

Background Multivariate pattern analysis is an alternative method of analyzing functional magnetic resonance imaging (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 general linear model (GLM)-based univariate analysis. Methods Nineteen 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 multivoxel 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 voxelwise activity across runs evaluated variance over time in activity patterns. Results Patients performed the task less accurately. This group difference was reflected in the pattern analysis results with diminished classification accuracy in patients compared with control subjects, 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 interrun correlations and classification accuracy. Conclusions 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 nonspecific factors driving these results.

Patients with schizophrenia have pronounced deficits in memory for events--episodic memory. These deficits severely affect patients' quality of life and functional outcome, and current medications have only a modest effect, making episodic memory an important domain for translational development of clinical trial paradigms. The current article provides a brief review of the significant progress that cognitive neuroscience has made in understanding basic mechanisms of episodic memory formation and retrieval that were presented and discussed at the first CNTRICS (Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia) meeting in Washington, D.C. During that meeting a collaborative decision was made that measures of item-specific and relational memory were the most promising constructs for immediate translational development. A brief summary of research on episodic memory in schizophrenia is presented to provide a context for investigating item-specific and relational memory processes. Candidate brain regions are also discussed.

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.Twelve 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).

Modafinil (2-[(Diphenylmethyl) sulfinyl] acetamide, Provigil) is an FDA-approved medication with wake-promoting properties. Pre-clinical studies of modafinil suggest a complex profile of neurochemical and behavioral effects, distinct from those of amphetamine. In addition, modafinil shows initial promise for a variety of off-label indications in psychiatry, including treatment-resistant depression, attention-deficit/hyperactivity disorder, and schizophrenia. Cognitive dysfunction may be a particularly important emerging treatment target for modafinil, across these and other neuropsychiatric disorders. We aimed to comprehensively review the empirical literature on neurochemical actions of modafinil, and effects on cognition in animal models, healthy adult humans, and clinical populations. We searched PubMed with the search term 'modafinil' and reviewed all English-language articles for neurochemical, neurophysiological, cognitive, or information-processing experimental measures. We additionally summarized the pharmacokinetic profile of modafinil and clinical efficacy in psychiatric patients. Modafinil exhibits robust effects on catecholamines, serotonin, glutamate, gamma amino-butyric acid, orexin, and histamine systems in the brain. Many of these effects may be secondary to catecholamine effects, with some selectivity for cortical over subcortical sites of action. In addition, modafinil (at well-tolerated doses) improves function in several cognitive domains, including working memory and episodic memory, and other processes dependent on prefrontal cortex and cognitive control. These effects are observed in rodents, healthy adults, and across several psychiatric disorders. Furthermore, modafinil appears to be well-tolerated, with a low rate of adverse events and a low liability to abuse. Modafinil has a number of neurochemical actions in the brain, which may be related to primary effects on catecholaminergic systems. These effects are in general advantageous for cognitive processes. Overall, modafinil is an excellent candidate agent for remediation of cognitive dysfunction in neuropsychiatric disorders.

Drug discovery and development in psychiatry is beset by many challenges, both those which are associated with the development process in general (and affecting all of medicine) and others, which are unique to psychiatry. Due to these factors, marginal progress has been achieved in the past as many features of serious mental illness remain untouched by existing treatments. Arguably, the most important of these drug targets is cognitive dysfunction, which strongly predicts clinical outcome in a number of major neuropsychiatric conditions. Therefore, a critical need exists for progress in the characterization of this and other targets for drug discovery and development. A key area, which is already showing promise, is the use of non-invasive functional neuroimaging to investigate both cognitive dysfunction and its remediation with novel agents. In this article, the authors describe the paradigmatic case of cognitive dysfunction in schizophrenia, and the prospects for using functional magnetic resonance imaging (fMRI) to investigate the effects of agents targeting cognition. The authors observe a number of advantages of this approach over other methodologies, as well as some significant issues to be resolved in the application of this technology. The authors propose that pharmaco-fMRI is emerging as a major tool to enhance the drug development process in order to bring truly novel treatments to patients with a range of neuropsychiatric disorders.

Background Excessive emotional responding is considered to be a hallmark of borderline personality disorder (BPD). The affect-modulated startle response is a reliable indicator of emotional processing of stimuli. The aim of this study was to examine emotional processing in BPD patients (n = 27) and healthy control subjects (n = 21). Methods Participants viewed an intermixed series of unpleasant, borderline-salient (e.g., “hate”), and neutral (e.g., “view”) words and were instructed to think about the meaning of the word for them personally while eyeblink responses were assessed. Results The BPD patients exhibited larger startle eyeblink during unpleasant but not neutral words, indicating exaggerated physiological affect. This finding remained significant when we controlled for comorbid diagnoses, including generalized anxiety disorder and post-traumatic stress disorder. Greater symptom severity was associated with greater affective-startle difference scores (unpleasant-neutral). Conclusions Consistent with the symptom of affective dysregulation, these results suggest an abnormality in the processing of unpleasant emotional stimuli by BPD patients.

Abstract. Background: Suicide is prevalent in schizophrenia (SZ), yet the neural system functions that confer suicide risk remain obscure. Circuits operated by the prefrontal cortex (PFC) are altered in SZ, including those that support reactive control, and PFC changes are observed in postmortem studies of heterogeneous suicide victims. Aims: We tested whether history of suicide attempt is associated with altered frontal motor cortex activity during reactive control processes. Method: We evaluated 17 patients with recent onset of DSM-IV-TR-defined SZ using the Columbia Suicide Severity Rating Scale and functional magnetic resonance imaging during Stroop task performance. Group-level regression models relating past suicidal behavior to frontal activation controlled for depression, psychosis, and impulsivity. Results: Past suicidal behavior was associated with relatively higher activation in the left-hemisphere supplementary motor area (SMA), pre-SMA, premotor cortex, and dorsolateral PFC, all ipsilateral to the active primary motor cortex. Conclusion: This study provides unique evidence that suicidal behavior in patients with recent-onset SZ directly relates to frontal motor cortex activity during reactive control, in a pattern reciprocal to the relationship with proactive control found previously. Further work should address how frontal-based control functions change with risk over time, and their potential utility as a biomarker for interventions to mitigate suicide risk in SZ.

Objective Suicide is highly-prevalent in major mood disorders, yet it remains unclear how suicidal ideation and suicidal behavior relate to brain functions, especially those that support control processes. We evaluated how prefrontal cortex (PFC) activity during goal-representation (an important component of cognitive control) relates to past suicidal ideation and behavior in patients with psychotic major mood disorders. Method 30 patients with recent-onset of either DSM-IV-TR-defined bipolar disorder type I ( n =21) or major depressive disorder ( n =9) with psychotic features, but neither in a major mood episode nor acutely psychotic at study, were evaluated for past suicidal ideation and behavior (Columbia Suicide Severity Rating Scale) and functional MRI during cognitive control task performance. Group-level regression models of brain activation accounted for current depression, psychosis and trait impulsivity. Results Intensity of past suicidal ideation was associated with higher control-related activation in right-hemisphere regions including the ventrolateral PFC (VLPFC) and orbitofrontal cortex, rostral insula, and dorsal striatum. Among those with past suicidal ideation ( n =16), past suicidal behavior ( n =8) was associated with higher control-related activation in right-hemisphere regions including VLPFC, rostrolateral PFC, and frontal operculum/rostral insula; and relatively lower activity in midline parietal regions, including cuneus and precuneus. Limitations The sample size of subjects with past suicidal behavior was modest, and all subjects were taking psychotropic medication. Conclusions This study provides unique evidence that in early-course psychotic major mood disorders, suicidal ideation and behavior histories directly relate to PFC-based circuit function in support of cognitive control.

Source memory is impaired in schizophrenia, and this deficit is related to symptoms of interpersonal antagonism such as suspiciousness and hostility. The present study evaluated source memory in borderline personality disorder (BPD) and its relation to interpersonal antagonism. Forty-one noninpatient adults with BPD according to the DSM-IV and 26 healthy control subjects performed a verbal source memory test requiring completion of sentences with and without emotional content ("Hot" vs. "Cold" sentences). Subjects also completed self-report measures of suspiciousness and interpersonal antagonism (Buss-Durkee Hostility Inventory) and depression (Beck Depression Inventory). The BPD group showed no significant difference from the control group in self-referential source memory, recognition memory, response bias, and performance enhancement for items with emotion content. However, in the BPD group, poorer self-referential source memory was significantly related to Hostility measures including suspiciousness, but not with Depression scores. In contrast, generic item recognition memory was unrelated to Hostility. Heterogeneity in source memory function may be specifically related to some of the hallmark interpersonal disturbances of BPD, independent of the effects of general negative affect or general memory impairment.

Impulsive aggression is associated with central serotonergic dysfunction. Animal models particularly implicate the 5-HT(1A) receptor in this behavior. We tested the hypothesis that central 5-HT(1A) receptor function is impaired in impulsive aggressive personality disorder patients. A total of 52 individuals with DSM-III-R personality disorders, all medically healthy adult outpatients without concurrent psychiatric medication treatment, underwent serial plasma cortisol, prolactin, and temperature measurements before and after ipsapirone 20 mg oral administration. Subjects completed self-report measures of impulsivity, hostility, depression and anxiety, and childhood maltreatment. Stepwise regression analysis revealed impulsivity alone among symptom measures to be associated with significantly decreased peak cortisol and prolactin responses. Diagnoses of borderline personality disorder (BPD) and intermittent explosive disorder-revised (IED-R) were associated with significantly increased and decreased cortisol responses, respectively. However, post hoc analyses indicated that impulsivity was significantly negatively correlated with cortisol responses in the BPD group, and may mediate the association of both BPD and IED-R with altered cortisol responses. Temperature response was associated with neither diagnostic nor symptom measures. Neither diagnostic nor dimensional measures of depression or anxiety, nor severity of childhood maltreatment, were significantly associated with cortisol, prolactin, or temperature responses. Impulsivity is related to impaired function at (or downstream to) postsynaptic 5-HT(1A) receptors, and this relationship may be partly responsible for the association of impaired serotonergic function with diagnoses such as BPD and IED-R. In addition, D(2) receptor dysfunction may play a role in impulsivity, whereas 5-HT(1A) cell-body autoreceptor function may be spared in these disorders.

The authors' goals were 1) to establish a clinically useful standard index of the relative anticholinergic potency of psychiatric medications; 2) to determine which cognitive functions are most affected by the administration of anticholinergic medications to patients with schizophrenia; and 3) to compare in vitro and clinically derived indexes of anticholinergic load in predicting these cognitive impairments.One hundred six clinically stable patients with schizophrenia were given a brief neuropsychological battery and evaluated on a standard symptom rating scale. The anticholinergic load associated with their psychiatric medications was estimated by using 1) a pharmacological index, calculated from a compilation of published studies reporting in vitro brain muscarinic receptor antagonism, and 2) a clinical index, based on clinician ratings of the anticholinergic side effects of medications. The authors analyzed the correlations of both indexes with the neuropsychological measures and with summary neuropsychological factor scores.The clinical and pharmacological anticholinergic indexes were highly correlated with each other and showed virtually identical associations with neuropsychological measures. Anticholinergic load was associated with lower scores on measures of attention and declarative memory, including several measures of auditory and visual memory and two tests of complex attention, but was unrelated to intelligence, simple attention, working memory, executive functions, conceptual fluency, or motor speed.This pattern of cognitive impairment with central cholinergic antagonism is consistent with emerging models of the functional anatomy of ascending forebrain cholinergic subsystems. Both pharmacological and clinical indexes show utility in predicting the effects of anticholinergic load on cognition in schizophrenia. Doses of psychiatric medication within the range of routine pharmacotherapy practice may have clinically significant effects on memory and complex attention in patients with schizophrenia; these effects may contribute as much as one-third to two-thirds of the memory deficit typically seen in patients with schizophrenia.

This study addressed the relationship of both semantic priming and slowed lexical access to the symptoms of schizophrenia, and evaluated their association with other neurocognitive deficits.57 outpatients with schizophrenia and 20 nonpsychiatric control subjects performed a lexical decision semantic priming task (LDT), and a brief neuropsychological battery. The schizophrenia group was also assessed with an extended Positive and Negative Symptom Scale.As expected, the schizophrenia group had significantly slower reaction times (RTs) than the control group, and poorer performance on most neuropsychological tasks. Both groups exhibited semantic priming effects in both automatic and controlled processing conditions; these effects were not significantly different between groups. RT was unrelated to age, illness duration, GAF scores, or neuroleptic dose; controlled semantic priming effects were related to illness duration only. RT to real word targets (but not to nonwords) on the LDT was significantly correlated with positive and disorganised, but not negative symptoms. The neurocognitive correlates of RT slowing were: full-scale IQ and verbal fluency, but not attention; working memory; episodic memory retrieval; executive function, or manual speed. Both controlled semantic priming effects as well as the difference between controlled and automatic priming effects were related to executive functions in general. Severity of symptoms in the three major symptom groups was generally unassociated with impairment on the neuropsychological battery. The associations of RT slowing to positive and disorganised symptoms remained even after controlling for each of the above clinical and neurocognitive measures.These findings suggest that in schizophrenia, slowed lexical access is uniquely related to positive and disorganised symptoms. This relationship is not accounted for by more general cognitive deficits, overall illness severity, or generalised effects of symptoms on cognitive function. This relationship may reflect a specific impairment in the access to semantic memory.

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.

The widely cited prefrontal dysfunction – excess subcortical dopamine model of schizophrenia posits that prefrontal deficits give rise to cognitive impairments and the disinhibition of subcortical dopamine release underlying psychosis. While this has been one of the most influential schizophrenia models, only a handful of studies have provided evidence supporting it directly in patients with schizophrenia. We previously demonstrated task-evoked substantia nigra hyperactivity in the context of prefrontal hypofunction and prefrontonigral functional disconnectivity. In addition, nigrostriatal functional connectivity was identified as a potential marker of psychosis. Because patients in this prior study had chronic schizophrenia and were treated with antipsychotics, in the present study we tested whether these findings were confounded by illness chronicity and medication effects by seeking to reproduce these findings in an independent sample of antipsychotic naïve, first episode (FE) patients. We compared event-related fMRI activations from12 FE patients with 15 demographically matched healthy control subjects during cognitive testing. We found substantia nigra hyperactivity associated with prefrontal hypofunction and prefrontonigral functional disconnectivity, as well as the magnitude of nigrostriatal functional connectivity positively correlating with severity of psychosis. This study adds to the body of evidence supporting the prefrontal – dopamine model of schizophrenia and further validates nigrostriatal functional connectivity as a marker of psychosis.

© 2014 Elsevier B.V. The majority of studies examining self-reported anticipatory and consummatory pleasure in schizophrenia, as measured on the Temporal Experience of Pleasure Scale (TEPS), have been conducted on chronically ill people with the disorder. In this study, people with a recent-onset schizophrenia spectrum diagnosis (first psychotic episode within one year of study participation) (. n=. 88) and people without a schizophrenia spectrum diagnosis (. n=. 66) were administered the TEPS. People with a schizophrenia spectrum diagnosis reported significantly lower scores of anticipatory, but not consummatory, pleasure on the TEPS compared to the control group. TEPS anticipatory pleasure scores were also significantly, negatively correlated with negative symptoms, but neither TEPS anticipatory nor consummatory pleasure scores were significantly correlated with functioning measures. Our results replicate previous findings with chronically ill people with schizophrenia on the TEPS.

Objective Suicide is highly-prevalent and the most serious outcome in schizophrenia, yet the disturbances in neural system functions that confer suicide risk remain obscure. Circuits operated by the prefrontal cortex (PFC) are altered in psychotic disorders, and various PFC changes are observed in post-mortem studies of completed suicide. We tested whether PFC activity during goal-representation (an important component of cognitive control) relates to long-term suicide risk in recent-onset schizophrenia. Method 35 patients with recent-onset of DSM-IV-TR-defined schizophrenia (SZ) were evaluated for long-term suicide risk (using the Columbia Suicide Severity Rating Scale) and functional MRI during cognitive control task performance. Group-level regression models associating control-related brain activation with suicide risk controlled for depression, psychosis and impulsivity. Results Within this group, past suicidal ideation was associated with lower activation with goal-representation demands in multiple PFC sectors. Among those with past suicidal ideation (n = 18), reported suicidal behavior was associated with lower control-related activation in premotor cortex ipsilateral to the active primary motor cortex. Conclusions This study provides unique evidence that suicide risk directly relates to PFC-based circuit dysfunction during goal-representation, in a major mental illness with significant suicide rates. Among those with suicidal ideation, the overt expression in suicidal behavior may stem from impairments in premotor cortex support of action-planning as an expression of control. Further work should address how PFC-based control function changes with risk over time, whether this brain–behavior relationship is specific to schizophrenia, and address its potential utility as a biomarker for interventions to mitigate suicide risk.

Models of cognitive control posit a key modulatory role for the pontine locus coeruleus–norepinephrine (LC-NE) system. In nonhuman primates, phasic LC-NE activity confers adaptive adjustments in cortical gain in task-relevant brain networks, and in performance, on a trial-by-trial basis. This model has remained untested in humans. We used the pharmacological agent modafinil to promote low-tonic/high-phasic LC-NE activity in healthy humans performing a cognitive control task during event-related functional magnetic resonance imaging (fMRI). Modafanil administration was associated with decreased task-independent, tonic LC activity, increased task-related LC and prefrontal cortex (PFC) activity, and enhanced LC-PFC functional connectivity. These results confirm in humans the role of the LC-NE system in PFC function and cognitive control and suggest a mechanism for therapeutic action of procognitive noradrenergic agents.

Impaired functional connectivity has been hypothesized as a potential source of the cognitive deficits routinely observed in patients with schizophrenia. Additionally, these deficits may be manifestations of the genetic liability to schizophrenia and present in the non-psychotic first-degree relatives of that group. However, no study has examined task-based functional connectivity in schizophrenia relatives using independent component analysis (ICA). We employed group ICA to test the hypothesis that the unexpressed genetic liability to schizophrenia is reflected in the functional connectivity between brain regions during a task measuring context processing. We compared 20 schizophrenia patients and 32 patients' first-degree relatives to 22 controls demographically matched to the patients and 28 controls' relatives, respectively. The group ICA showed differential connectivity between patients and controls in a task-related network constituting right middle frontal gyrus (MFG) and right posterior parietal lobe. A network constituting left MFG and left posterior parietal, which was also related to the context processing task, did not differ between groups. These findings demonstrate that connectivity abnormalities associated with the genetic liability to schizophrenia are most strongly expressed in a right lateralized executive fronto-parietal network, and that these abnormalities are linked to context processing impairments.

Background The theory that prefrontal cortex (PFC) dysfunction in schizophrenia leads to excess subcortical dopamine 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 functional magnetic resonance imaging study to test the hypothesis that PFC dysfunction is associated with altered function of and connectivity with dopamine regulating regions of the basal ganglia. Methods Eighteen individuals with schizophrenia or schizoaffective disorder and 19 healthy control participants completed event-related functional magnetic resonance imaging 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. Results 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. Conclusions These results suggest that functional impairments of the prefrontal striatonigral circuit may be a common pathway linking the pathogenesis of cognitive deficits and psychosis in schizophrenia.