Impact of the KCNQ2/3 Channel Opener Ezogabine on Reward Circuit Activity and Clinical Symptoms in Depression: Results From a Randomized Controlled Trial.

OBJECTIVE: Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression. METHODS: Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24). Participants underwent functional MRI during a reward flanker task at baseline and following treatment. Clinical measures of depression and anhedonia were collected at weekly visits. The primary endpoint was the change from baseline to week 5 in ventral striatum activation during reward anticipation. Secondary endpoints included depression and anhedonia severity as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively. RESULTS: The study did not meet its primary neuroimaging endpoint. Participants in the ezogabine group showed a numerical increase in ventral striatum response to reward anticipation following treatment compared with participants in the placebo group from baseline to week 5. Compared with placebo, ezogabine was associated with a significantly larger improvement in MADRS and SHAPS scores and other clinical endpoints. Ezogabine was well tolerated, and no serious adverse events occurred. CONCLUSIONS: The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted.

Schizophrenia and bipolar disorder are associated with opposite brain reward anticipation-associated response.

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.

Reaction time variability and related brain activity in methamphetamine psychosis.

BACKGROUND: This study investigated the dynamics of cognitive control instability in methamphetamine (MA) abuse, as well its relationship to substance-induced psychiatric symptoms and drug use patterns. METHODS: We used an ex-Gaussian reaction time (RT) distribution to examine intraindividual variability (IIV) and excessively long RTs (tau) in an individual's RT on a Stroop task in 30 currently drug-abstinent (3 months to 2 years) MA abusers compared with 27 nonsubstance-abusing control subjects. All subjects underwent functional magnetic resonance imaging while performing the Stroop task, which allowed us to measure the relationship between IIV and tau to functional brain activity. RESULTS: Elevated IIV in the MA compared with the control group did not reach significance; however, when the MA group was divided into those subjects who had experienced MA-induced psychosis (MAP+) (n = 19) and those who had not (n = 11), the MAP+ group had higher average IIV compared with the other groups (p < .03). In addition, although control subjects displayed a relationship between IIV and conflict-related brain activity in bilateral prefrontal cortex such that increased IIV was associated with increased activity, the MAP+ group displayed this relationship in right prefrontal cortex only, perhaps reflecting elevated vigilance in the MAP+ group. Greater IIV did not correlate with severity of use or months MA abstinent. No group differences emerged in tau values. CONCLUSIONS: These results suggest increased cognitive instability in those MA-dependent subjects who had experienced MA-induced psychosis.

Predictors of methamphetamine psychosis: history of ADHD-relevant childhood behaviors and drug exposure.

The goal of this study was to extend our previous research that reported a significant association between Attention Deficit Hyperactivity Disorder (ADHD)-relevant childhood behaviors and the frequency of methamphetamine (MA)-induced psychotic symptoms in an expanded sample. 190 participants who met DSM-IV criteria for MA dependence were administered the Methamphetamine Experience Questionnaire that assessed MA-induced psychosis. Data related to MA exposure, comorbid drug use, education, familial psychiatric history and assessments of ADHD-relevant childhood behaviors as measured by the Wender Utah Rating Scale (WURS) were collected. Although WURS scores did not differ between 145 MAP+ and 45 MAP- subjects, MAP+ subjects with higher WURS scores were significantly more likely to report more frequent psychosis. Although mean daily MA dosage did not differ between the MAP+ and MAP- subjects, MAP+ subjects who consumed larger doses of MA were significantly more likely to experience frequent psychosis. These data suggest that ADHD-relevant childhood behaviors may interact with MA exposure to reflect a neurobiological vulnerability related to the emergence of frequent MA-induced psychotic symptoms. These results may elucidate factors that contribute to the psychiatric sequelae of MA abuse.

Behavioral regulation in methamphetamine abusers: an fMRI study.

The goal of this study was to extend our previous findings of abnormal prefrontal function in methamphetamine (MA) abusers and controls and to link the imaging data to behavioral, demographic and drug use variables. We used a fast event-related functional magnetic resonance imaging (fMRI) design to examine trial-to-trial reaction time (RT) adjustments in 30 MA abusers and 30 controls. A variant of the Stroop task was employed to measure influence of response conflict on RT, including the level of trial-to-trial RT adjustments seen after conflict trials. Compared to control subjects, MA abusers exhibited reduced RT adjustments and reduced activation in the prefrontal cortex (PFC) after conflict trials. RT adjustment correlated negatively with PFC brain activity in the MA group, while a trend for a positive correlation was observed in controls. No correlations were observed between task performance or brain activity and age, education or drug use variables. These data support our previous findings that the ability to adapt a behavioral response based on prior experience is compromised in MA abusers. Interestingly, these impairments do not appear to be linked to drug use patterns or to educational levels.

Prefrontal cortical deficits and impaired cognition-emotion interactions in schizophrenia.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Diminished orientation-specific surround suppression of visual processing 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.

The neural substrates of cognitive control deficits in autism spectrum disorders.

Executive function deficits are among the most frequently reported symptoms of autism spectrum disorders (ASDs), however, there have been few functional magnetic resonance imaging (fMRI) studies that investigate the neural substrates of executive function deficits in ASDs, and only one in adolescents. The current study examined cognitive control - the ability to maintain task context online to support adaptive functioning in the face of response competition - in 22 adolescents aged 12-18 with autism spectrum disorders and 23 age, gender, and IQ matched typically developing subjects. During the cue phase of the task, where subjects must maintain information online to overcome a prepotent response tendency, typically developing subjects recruited significantly more anterior frontal (BA 10), parietal (BA 7 and BA 40), and occipital regions (BA 18) for high control trials (25% of trials) versus low control trials (75% of trials). Both groups showed similar activation for low control cues, however the ASD group exhibited significantly less activation for high control cues. Functional connectivity analysis using time series correlation, factor analysis, and beta series correlation methods provided convergent evidence that the ASD group exhibited lower levels of functional connectivity and less network integration between frontal, parietal, and occipital regions. In the typically developing group, fronto-parietal connectivity was related to lower error rates on high control trials. In the autism group, reduced fronto-parietal connectivity was related to attention deficit hyperactivity disorder symptoms.

An initial investigation of the orbitofrontal cortex hyperactivity in obsessive-compulsive disorder: exaggerated representations of anticipated aversive events?

Orbitofrontal cortical (OFC) dysfunction has been repeatedly involved in obsessive-compulsive disorder, but the precise significance of this abnormality is still unclear. Current neurocognitive models propose that specific areas of the OFC contribute to behavioral regulation by representing the anticipated affective value of future events. This leads to the hypothesis that these OFC areas are hyperactive in patients, reflecting ruminative preoccupation with future aversive events. In experimental situations, such hyperactivity should be triggered by negative affect in response to high likelihood of events such as the conflict between simultaneously active incompatible responses, which can potentially lead to poor task performance. We tested this hypothesis by examining fMRI indices of brain activity of 15 OCD patients and 15 matched controls. Subjects were scanned while performing a cognitive task which involved responding to cues and subsequent probes, and some of the probes elicited response conflict. Relative to controls, the lateral OFC of patients was specifically hyperactive to cues associated with high proportion of subsequent high-conflict probes. The level of OFC hyperactivity correlated directly with the severity of anxiety symptoms. These results support the hypothesis that OCD is characterized by exaggerated OFC representations of anticipated aversive events.

Impaired prefrontal cortical function and disrupted adaptive cognitive control in methamphetamine abusers: a functional magnetic resonance imaging study.

BACKGROUND: Methamphetamine (MA) abuse is associated with neurotoxicity to frontostriatal brain regions with deleterious effects on cognitive processes. Deficits in behavioral control are thought to be one contributing factor to the sustainment of addictive behaviors in MA abuse. METHODS: In order to examine patterns of behavioral control relevant to addiction, we employed a fast-event-related functional magnetic resonance imaging design to examine trial-to-trial reaction time (RT) adjustments in 12 MA-dependent subjects and 16 non-substance-abusers. A variant of the Stroop task was employed to contrast the groups on error rates, RT conflict, and the level of trial-to-trial adjustments seen after incongruent trials. RESULTS: The MA abusers exhibited reduced RT adjustments and reduced activation in the right prefrontal cortex compared to controls on conditions that measured the ability to use exposure to conflict situations (i.e., conflict trials) to regulate behavior. The groups did not differ on accuracy rates or within-trial Stroop conflict effects. CONCLUSIONS: The observed deficits in trial-to-trial RT adjustments suggest that the ability to adapt a behavioral response based on prior experience may be compromised in MA abusers. These failures to modify behavior based on prior events may reflect a deficit that contributes to drug-seeking behavior.

Conflict-related activity in the caudal anterior cingulate cortex in the absence of awareness.

The caudal anterior cingulate cortex (cACC) is thought to be involved in performance monitoring, as conflict and error-related activity frequently co-localize in this area. Recent results suggest that these effects may be differentially modulated by awareness. To clarify the role of awareness in performance monitoring by the cACC, we used rapid event-related fMRI to examine the cACC activity while subjects performed a dual task: a delayed recognition task and a serial response task (SRT) with an implicit probabilistic learning rule (i.e. the stimulus location followed a probabilistic sequence of which the subjects were unaware). Task performance confirmed that the location sequence was learned implicitly. Even though we found no evidence of awareness for the presence of the sequence, imaging data revealed increased cACC activity during correct trials which violated the sequence (high-conflict), relative to trials when stimuli followed the sequence (low conflict). Errors made with awareness also activated the same brain region. These results suggest that the performance monitoring function of the cACC extends beyond detection of errors made with or without awareness, and involves detection of multiple responses even when they are outside of awareness.

Modafinil shifts human locus coeruleus to low-tonic, high-phasic activity during functional MRI.

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.

Multivariate pattern analysis of functional magnetic resonance imaging data reveals deficits in distributed representations 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.

Distinguishing expected negative outcomes from preparatory control in the human orbitofrontal cortex.

The human orbitofrontal cortex (OFC) plays a critical role in adapting behavior according to the context provided by expected outcomes of actions. However, several aspects of this function are still poorly understood. In particular, it is unclear to what degree any subdivisions of the OFC are specifically engaged when negatively valenced outcomes are expected, and to what extent such areas might be involved in preparatory active control of behavior. We examined these issues in two complementary functional magnetic resonance imaging (fMRI) studies in which we simultaneously and independently manipulated monetary incentives for correct performance, and demands for active preparation of cognitive control. In both experiments, preparation for performance was associated with lateral PFC activity in response to high incentives, regardless of their valence, as well as in response to increased task demands. In contrast, areas of the OFC centered around the lateral orbital sulcus responded maximally to negatively perceived prospects, even when such prospects were associated with decreases in preparatory cognitive control. These results provide direct support for theoretical models which posit that the OFC contributes to behavioral regulation by representing the value of anticipated outcomes, but does not implement active control aimed at avoiding or pursuing outcomes. Furthermore, they provide additional converging evidence that the lateral OFC is involved in representing specifically the affective impact of anticipated negative outcomes.

Association of dorsolateral prefrontal cortex dysfunction with disrupted coordinated brain activity in schizophrenia: relationship with impaired cognition, behavioral disorganization, and global function.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

Outcome representations, counterfactual comparisons and the human orbitofrontal cortex: implications for neuroimaging studies of decision-making.

Recent research suggests that the primate orbitofrontal cortex (OFC) is critical for representations of outcomes of actions and their subsequent impact on the control of behavior. In parallel, a recent theory of decision-making called decision affect theory (Mellers, Schwartz, and Ritov, Psychological Science, 1997) emphasizes the role of anticipated affective impact of outcomes in guiding choices, and the effects of comparisons with alternative outcomes (i.e., counterfactual effects). In the context of decision affect theory, we present results from two event-related functional MRI experiments consistent with two hypotheses regarding the role of the human OFC in guiding behavior through outcome representation: (1) counterfactual effects are manifested in the human OFC during expectation of outcomes, such that the anticipated affective impact of outcomes is modulated by the nature of the various possible alternative outcomes; (2) a regional specialization exists in the human prefrontal cortex, such that affective impact of potential negative outcomes of actions is represented mainly by the lateral areas of the OFC, while areas situated progressively more medial and dorsal on the ventral and medial PFC are specifically involved in representing the impact of positively valenced outcomes. We also discuss some of the implications that these hypotheses have for neuroimaging studies of reward processing and decision-making, and for studies of neuropsychiatric disorders in which these processes are thought to be disturbed.

Specificity of prefrontal dysfunction and context processing deficits to schizophrenia in never-medicated patients with first-episode psychosis.

OBJECTIVE: Context processing is a cognitive construct associated with activity in the middle frontal gyrus. Schizophrenia-related deficits in context processing tasks have been associated with prefrontal cortical dysfunction. This study evaluated whether prefrontal cortical dysfunction related to context processing occurred in first-episode, never-medicated schizophrenia patients, whether this dysfunction also occurred in patients with nonschizophrenia psychosis, and whether this dysfunction was related to psychotic symptom expression. METHOD: A modified version of the AX continuous performance task was conducted during event-related functional magnetic resonance imaging in 18 never-medicated, first-episode schizophrenia patients, 12 never-medicated patients with first-episode nonschizophrenia psychosis, and 28 comparison participants without psychiatric disorder. RESULTS: In-scanner measures of errors and interference reaction time showed that the schizophrenia patients had a specific deficit in context processing. Trials with greater context processing demands corresponded to activity in the middle frontal gyrus (Brodmann's area 9) in the comparison subjects and in the patients with nonschizophrenia psychosis, but not in the schizophrenia patients. Individual differences in prefrontal cortical dysfunction were associated with context processing measures and disorganization symptoms. The schizophrenia patients also showed increased activity in the anterior (Brodmann's area 10) and inferior prefrontal cortices (Brodmann's area 45/46) when they were maintaining context over a delay. CONCLUSIONS: Prefrontal dysfunctions related to context processing were found only in schizophrenia patients early in the course of the illness, and these dysfunctions were related to disorganization symptoms. Instead of using context processing during a continuous performance task, schizophrenia patients may use an inefficient encoding and retrieval strategy.

Overactive action monitoring in obsessive-compulsive disorder: evidence from functional magnetic resonance imaging.

The anterior cingulate cortex (ACC) in patients with obsessive-compulsive disorder (OCD) has been found to be hyperactive at rest, during symptom provocation, and after commission of errors in cognitive tasks. This hyperactivity might reflect an abnormality in conflict detection, a hypothesized basic mechanism for the action-monitoring function of the ACC. This hypothesis was tested using functional magnetic resonance imaging, by scanning 11 OCD patients and 13 matched control subjects while they performed a version of the continuous-performance task with four trial types that induced graded levels of response conflict. Although a behavioral index of conflict (i.e., accuracy) was similar for patients and control subjects, the ACC activation was increased in patients during high-conflict trials. The error-related activity in the same brain region was also higher in patients, consistent with previous electrophysiological findings. Both conflict- and error-related activity showed trends for positive correlations with severity of OCD symptoms, but not with anxiety. These findings suggest that as part of an overactive action-monitoring system, the ACC is more directly involved in the pathophysiology of OCD than previously thought.