Expression of four housekeeping proteins in elderly patients with schizophrenia

We compared protein expression by Western blot analysis in four areas of postmortem brain from patients with schizophrenia and control subjects for several proteins that are often used as controls for Western blot studies: β-tubulin, actin, glyceraldehyde-3-phosphate dehydrogenase, and valosin-containing protein. We did not detect any differences in expression between subjects with schizophrenia and a comparison group. These results suggest that all four proteins are suitable loading controls for postmortem studies of schizophrenia. Supported by MH53327 (JMW), MH78378 (DEB), MH064673 & MH066392 (VH) and MH074016 (REM).     

Shorter sleep duration is associated with lower GABA levels in the anterior cingulate cortex

BackgroundAlterations in the levels of gamma-aminobutyric acid (GABA) and glutamate + glutamine (Glx), which are major inhibitory and excitatory neurotransmitters, respectively, are frequently associated with insomnia. Previous reports also suggested the involvement of the anterior cingulate cortex (ACC) and medial prefrontal cortex (mPFC) in insomnia and shorter sleep duration. In the current study, we investigated whether the GABA and Glx levels were altered in the ACC/mPFC in subclinical insomnia while focusing on the sleep duration.MethodsWe examined levels of GABA and Glx in the ACC/mPFC of the brain with magnetic resonance spectroscopy in 166 individuals with subjective sleep complaints but without a diagnosis of insomnia. Participants were divided into two groups according to sleep duration (≥6 h/night: n = 79 vs. < 6 h/night: n = 74), which was measured using a wrist-worn actigraphy. Working memory function and overall subjective sleep quality were assessed with a computerized neuropsychological test and self-report questionnaire, respectively.ResultsGABA levels in the ACC/mPFC were lower in the shorter sleep duration group relative to the longer sleep duration group (t = −2.21, p = 0.03). Glx levels did not differ between the two groups (t = −0.20, p = 0.84). Lower GABA levels were associated with lower spatial working memory performance in the shorter sleep duration group (β = −0.21, p = 0.03), but not the longer sleep duration group (β = 0.04, p = 0.72).ConclusionShorter sleep duration was associated with lower GABA levels in the ACC/mPFC. These findings may provide insight into the underlying mechanisms of impaired working memory function related to insomnia and sleep loss.     

Magnetic stimulation of the dorsolateral prefrontal cortex dissociates fragile visual short-term memory from visual working memory

To guide our behavior in successful ways, we often need to rely on information that is no longer in view, but maintained in visual short-term memory (VSTM). While VSTM is usually broken down into iconic memory (brief and high-capacity store) and visual working memory (sustained, yet limited-capacity store), recent studies have suggested the existence of an additional and intermediate form of VSTM that depends on activity in extrastriate cortex. In previous work, we have shown that this fragile form of VSTM can be dissociated from iconic memory. In the present study, we provide evidence that fragile VSTM is different from visual working memory as magnetic stimulation of the right dorsolateral prefrontal cortex (DLPFC) disrupts visual working memory, while leaving fragile VSTM intact. In addition, we observed that people with high DLPFC activity had superior working memory capacity compared to people with low DLPFC activity, and only people with high DLPFC activity really showed a reduction in working memory capacity in response to magnetic stimulation. Altogether, this study shows that VSTM consists of three stages that have clearly different characteristics and rely on different neural structures. On the methodological side, we show that it is possible to predict individual susceptibility to magnetic stimulation based on functional MRI activity.     

A functional magnetic resonance imaging study of working memory abnormalities in schizophrenia.

BACKGROUND: Previous neuroimaging studies of working memory (WM) in schizophrenia, typically focusing on dorsolateral prefrontal cortex, yield conflicting results, possibly because of varied choice of tasks and analysis techniques. We examined neural function changes at several WM loads to derive a more complete picture of WM dysfunction in schizophrenia. METHODS: We used a version of the Sternberg Item Recognition Paradigm to test WM function at five distinct loads. Eighteen schizophrenia patients and 18 matched healthy controls were scanned with functional magnetic resonance imaging at 3 Tesla. RESULTS: Patterns of both overactivation and underactivation in patients were observed depending on WM load. Patients' activation was generally less responsive to load changes than control subjects', and different patterns of between-group differences were observed for memory encoding and retrieval. In the specific case of successful retrieval, patients recruited additional neural circuits unused by control subjects. Behavioral effects were generally consistent with these imaging results. CONCLUSIONS: Differential findings of overactivation and underactivation may be attributable to patients' decreased ability to focus and allocate neural resources at task-appropriate levels. Additionally, differences between encoding and retrieval suggest that WM dysfunction may be manifested differently during the distinct phases of encoding, maintenance, and retrieval.     

Bilateral Transcranial Direct Current Stimulation Over Dorsolateral Prefrontal Cortex Changes the Drug-cued Reactivity in the Anterior Cingulate Cortex of Crack-cocaine Addicts

BackgroundPatients addicted to crack-cocaine routinely have difficulty sustaining treatment, which could be related to dysfunctional cerebral activity that occurs in addiction.ObjectiveTo investigate the indirect electrophysiological effects of single transcranial direct current stimulation (tDCS) on cocaine-addicted brains.MethodsThe patients received either left cathodal/right anodal or sham stimulation over the DLPFC. The region of interest was the anterior cingulate cortex (ACC) during the N2 time window (200–350 ms). Event-related potentials in the ACC were measured during visual presentation of crack-related cues or neutral cues.ResultsLow-resolution brain electromagnetic tomography (LORETA) indicated that exposure to crack-related images led to increased activity in the ACC in the sham group, while the tDCS group showed decreased ACC activity after visualization of drug cues.ConclusionPrefrontal tDCS specifically modulated the ACC response during exposure to visual drug cues in crack-cocaine users.     

Response conflict and frontocingulate dysfunction in unmedicated participants with major depression

Individuals with major depressive disorder (MDD) often exhibit impaired executive function, particularly in experimental tasks that involve response conflict and require adaptive behavioral adjustments. Prior research suggests that these deficits might be due to dysfunction within frontocingulate pathways implicated in response conflict monitoring and the recruitment of cognitive control. However, the temporal unfolding of conflict monitoring impairments in MDD remains poorly understood. To address this issue, we recorded 128-channel event-related potentials while 20 unmedicated participants with MDD and 20 demographically matched, healthy controls performed a Stroop task. Compared to healthy controls, MDD subjects showed larger Stroop interference effects and reduced N2 and N450 amplitudes. Source localization analyses at the time of maximal N450 activity revealed that MDD subjects had significantly reduced dorsal anterior cingulate cortex (dACC; Brodmann area 24/32) and left dorsolateral prefrontal cortex (Brodmann area 10/46) activation to incongruent relative to congruent trials. Consistent with the heterogeneous nature of depression, follow-up analyses revealed that depressed participants with the lowest level of conflict-related dACC activation 620 ms post-stimulus were characterized by the largest Stroop interference effects (relatively increased slowing and reduced accuracy for incongruent trials). Conversely, MDD participants with relatively stronger dACC recruitment did not differ from controls in terms of interference effects. These findings suggest that for some, but not all individuals, MDD is associated with impaired performance in trials involving competition among different response options, and reduced recruitment of frontocingulate pathways implicated in conflict monitoring and cognitive control.     

Strong correspondence between prefrontal and visual representations during emotional perception

Emotion is thought to cause focal enhancement or distortion of certain components of memory, indicating a complex property of emotional modulation on memory rather than simple enhancement. However, the neural basis for detailed modulation of emotional memory contents has remained unclear. Here has been shown that the information processing of the prefrontal cortex differentially affects sensory representations during experience of emotional information compared with neutral information, using functional magnetic resonance imaging (fMRI). It was found that during perception of emotional pictures, information representation in primary visual cortex (V1) significantly corresponded with the representations in dorsolateral prefrontal cortex (dlPFC). This correspondence was not observed for neutral pictures. Furthermore, participants with greater correspondence between visual and prefrontal representations showed better memory for high‐level semantic components but not for low‐level visual components of emotional stimuli. These results suggest that sensory representation during experience of emotional stimuli, compared with neutral stimuli, is more directly influenced by internally generated higher‐order information from the prefrontal cortex.     

Social appraisal in chronic psychosis: Role of medial frontal and occipital networks

Persons with schizophrenia often appraise other individuals as threatening or persecutory. To evaluate social appraisal in schizophrenia, we probed brain networks with a task in which subjects judged whether or not they liked face stimuli with emotional expressions. We predicted that appraising negative expressions would engage patients, more than controls, and negative faces would be related to higher levels of negative affect and produce increased activity in the medial frontal cortex, an area involved in social appraisal. Twenty-one stable outpatients with chronic non-affective psychosis (16 schizophrenic, 5 schizoaffective) and 21 healthy subjects underwent functional magnetic resonance imaging. Compared with the control subjects, patients were slower to respond, but particularly slow when they judged negatively-valenced faces, a slowness correlated with negative affect in the psychosis patients. Appraisal activated the medial prefrontal cortex (mPFC) across all face valences. For negative expressions, patients exhibited greater activation of the dorsal anterior cingulate cortex (dACC). A psychophysiological interaction analysis of the dACC revealed co-modulation of the mPFC in controls, significantly less in patients, and a trend for co-modulation of occipital cortex in the patients. Activity in occipital cortex correlated with poor social adjustment and impaired social cognition, and co-modulation of the occipital gyrus by the dACC was correlated with poorer social cognition. The findings link appraisal of negative affect with aberrant activation of the medial frontal cortex, while early sensory processing of this social cognitive task was linked with poor social function, reflecting either top-down or bottom-up influences.     

Brain activation underlying threat detection to targets of different races

The current study examined blood oxygen level-dependent signal underlying racial differences in threat detection. During functional magnetic resonance imaging, participants determined whether pictures of Black or White individuals held weapons. They were instructed to make shoot responses when the picture showed armed individuals but don’t shoot responses to unarmed individuals, with the cost of not shooting armed individuals being greater than that of shooting unarmed individuals. Participants were faster to shoot armed Blacks than Whites, but faster in making don’t shoot responses to unarmed Whites than Blacks. Brain activity differed to armed versus unarmed targets depending on target race, suggesting different mechanisms underlying threat versus safety decisions. Anterior cingulate cortex was preferentially engaged for unarmed Whites than Blacks. Parietal and visual cortical regions exhibited greater activity for armed Blacks than Whites. Seed-based functional connectivity of the amygdala revealed greater coherence with parietal and visual cortices for armed Blacks than Whites. Furthermore, greater implicit Black-danger associations were associated with increased amygdala activation to armed Blacks, compared to armed Whites. Our results suggest that different neural mechanisms may underlie racial differences in responses to armed versus unarmed targets.     

Targeting location relates to treatment response in active but not sham rTMS stimulation

BackgroundPrecise targeting of brain functional networks is believed critical for treatment efficacy of rTMS (repetitive pulse transcranial magnetic stimulation) in treatment resistant major depression.ObjectiveTo use imaging data from a “failed” clinical trial of rTMS in Veterans to test whether treatment response was associated with rTMS coil location in active but not sham stimulation, and compare fMRI functional connectivity between those stimulation locations.MethodsAn imaging substudy of 49 Veterans (mean age, 56 years; range, 27–78 years; 39 male) from a randomized, sham-controlled, double-blinded clinical trial of rTMS treatment, grouping participants by clinical response, followed by group comparisons of treatment locations identified by individualized fiducial markers on structural MRI and resting state fMRI derived networks.ResultsThe average stimulation location for responders versus nonresponders differed in the active but not in the sham condition (P = .02). The average responder location derived from the active condition showed significant negative functional connectivity with the subgenual cingulate (P < .001) while the nonresponder location did not (P = .17), a finding replicated in independent cohorts of 84 depressed and 35 neurotypical participants. The responder and nonresponder stimulation locations evoked different seed based networks (FDR corrected clusters, all P < .03), revealing additional brain regions related to rTMS treatment outcome.ConclusionThese results provide evidence from a randomized controlled trial that clinical response to rTMS is related to accuracy in targeting the region within DLPFC that is negatively correlated with subgenual cingulate. These results support the validity of a neuro-functionally informed rTMS therapy target in Veterans.     

Prefrontal activity and impaired memory encoding strategies in schizophrenia

Schizophrenia patients have significant memory difficulties that have far-reaching implications in their daily life. These impairments are partly attributed to an inability to self-initiate effective memory encoding strategies, but its core neurobiological correlates remain unknown. The current study addresses this critical gap in our knowledge of episodic memory impairments in schizophrenia. Schizophrenia patients (n = 35) and healthy controls (n = 23) underwent a Semantic Encoding Memory Task (SEMT) during an fMRI scan. Brain activity was examined for conditions where participants were a) prompted to use semantic encoding strategies, or b) not prompted but required to self-initiate such strategies. When prompted to use semantic encoding strategies, schizophrenia patients exhibited similar recognition performance and brain activity as healthy controls. However, when required to self-initiate these strategies, patients had significant reduced recognition performance and brain activity in the left dorsolateral prefrontal cortex, as well as in the left temporal gyrus, left superior parietal lobule, and cerebellum. When patients were divided based on performance on the SEMT, the subgroup with more severe deficits in self-initiation also showed greater reduction in left dorsolateral prefrontal activity. These results suggest that impaired self-initiation of elaborative encoding strategies is a driving feature of memory deficits in schizophrenia. We also identified the neural correlates of impaired self-initiation of semantic encoding strategies, in which a failure to activate the left dorsolateral prefrontal cortex plays a key role. These findings provide important new targets in the development of novel treatments aiming to improve memory and ultimately patients' outcome.     

Working memory deficits in schizophrenia are not necessarily specific or associated with MRI-based estimates of area 46 volumes

Despite substantial evidence that the prefrontal cortex does not function normally in patients diagnosed with schizophrenia, evidence for prefrontal structural abnormalities, as measured by magnetic resonance imaging (MRI), has been inconsistent. Additionally, evidence for relationships between prefrontal structural and functional measures has been limited. The inconsistencies in the MRI literature are, at least in part, due to a lack of standard and specific measurement protocols that allow delineation of functionally distinct cortical regions. In this study, reliable methods for measuring an estimate of area 46 (estimate referred to as area 46_e), as defined by ‘Cereb. Cortex 5 (1995) 323’, were developed and used to examine relationships between area 46_e volumes, working memory, and symptom severity in 23 male patients and 23 healthy male comparison subjects. Patients performed more poorly than healthy reference subjects on all cognitive measures including measures of spatial and non-spatial working memory, but showed no significant corresponding deficits in area 46_e volumes or whole brain volumes. Moreover, there were no significant relationships between symptom severity and area 46_e volumes. These findings suggest that the prefrontal functional abnormalities observed in schizophrenia may occur in the absence of prefrontal volume deficits, and may instead involve more widespread brain systems or prefrontal connections with other brain regions.     

Lateralized contribution of prefrontal cortex in controlling task-irrelevant information during verbal and spatial working memory tasks: rTMS evidence

The functional organization of working memory (WM) in the human prefrontal cortex remains unclear. The present study used repetitive transcranial magnetic stimulation (rTMS) to clarify the role of the dorsolateral prefrontal cortex (dlPFC) both in the types of information (verbal vs. spatial), and the types of processes (maintenance vs. manipulation). Subjects performed three independent experiments (1-back and 2-back tasks) while rTMS was applied over dlPFC for 500 ms in the last period of the delay. In two experiments (1 and 2) physically identical stimuli (letters shown at different locations on a screen) under different domain conditions (letters or locations) were employed. Under these conditions, we discovered a double dissociation only in the 2-back task: during the letter condition, when applied to the right dlPFC, rTMS significantly delayed task performance, whereas, the same result was present during the location condition, but only when rTMS was applied to the left dlPFC. The other 2-back task (experiment 3), in which we had eliminated the task-irrelevant information (i.e. we used stimuli that varied only in one domain), did not show significant results. We propose that the functional dichotomy of the hemispheres may be due to mechanisms of cognitive control on interference, which resolve conflict through the inhibition of task-irrelevant information only during high WM load. In conclusion, these findings confirm the role of dlPFC in implementing top-down attentional control, and provide evidence for the theoretical suggestion that working memory serves to control selective attention in the normal human brain.     

Altered error-related activity in patients with schizophrenia

Deficits in working memory (WM) and executive cognitive control are core features of schizophrenia. However, findings regarding functional activation strengths are heterogeneous, partly due to differences in task demands and behavioral performance. Previous investigators proposed integrating these heterogeneous findings into a comprehensive model of cortical inefficiency assuming the inverted U-shaped relationship between performance and neuronal activation to be shifted in patients.The present study pursued a novel approach of precise performance balancing potentially resolving a number of discrepancies with regard to performance related cognitive activation patterns in schizophrenia. Error-related WM activity was examined in 55 patients and 55 controls by balancing the mean number of incorrect responses between the groups and analyzing remaining incorrect trials. A modified Sternberg Item Recognition task (SIRT) allowing for the segregation of encoding, executive maintenance and retrieval-related activation was applied.Relative to healthy controls, patients showed extended hypoactivations in inferior temporal, superior parietal, inferior, middle and superior frontal as well as cerebellar regions during encoding of incorrectly remembered items. During erroneous retrieval of information patients exhibited a significantly decreased activation in an executive control network comprising inferior and middle frontal areas, precuneus and cerebellum.Present data suggest that in patients with schizophrenia encoding of erroneously retrieved items as well as erroneous retrieval itself is associated with extended activation abnormalities in task-relevant regions even after balancing performance. Thus, present results clearly indicate that disorder-characteristic activation abnormalities become manifest during dysfunctional executive processing even when the moderating effect of performance is largely eliminated.     

Neural correlates of refixation saccades and antisaccades in normal and schizophrenia subjects.

BACKGROUND: Schizophrenia subjects demonstrate difficulties on tasks requiring saccadic inhibition, despite normal refixation saccade performance. Saccadic inhibition is ostensibly mediated via prefrontal cortex and associated cortical/subcortical circuitry. The current study tests hypotheses about the neural substrates of normal and abnormal saccadic performance among subjects with schizophrenia. METHODS: Using functional magnetic resonance imaging, blood oxygenation level-dependent (BOLD) data were recorded while 13 normal and 14 schizophrenia subjects were engaged in refixation and antisaccade tasks. RESULTS: Schizophrenia subjects did not demonstrate the increased prefrontal cortex BOLD contrast during antisaccade performance that was apparent in the normal subjects. Schizophrenia subjects did, however, demonstrate normal BOLD contrast associated with refixation saccade performance in the frontal and supplementary eye fields, and posterior parietal cortex. CONCLUSIONS: Results from the current study support hypotheses of dysfunctional prefrontal cortex circuitry among schizophrenia subjects. Furthermore, this abnormality existed despite normal BOLD contrast observed during refixation saccade generation in the schizophrenia group.     

Dorsolateral prefrontal cortex volume in patients with deficit or nondeficit schizophrenia

Deficit schizophrenia (DS) represents a promising putative clinical subtype of schizophrenia and is characterized by the presence of primary and enduring negative symptoms. Previous studies have often reported a reduced amount of gray matter within prefrontal and temporal cortices in schizophrenia subjects with prevailing negative symptoms; however, the evidence concerning brain structural abnormalities in patients with DS remains controversial. The aim of the present study was to investigate whether patients with DS differed from those with nondeficit schizophrenia (NDS) with respect to the volume of the dorsolateral prefrontal cortex (DLPFC) and hippocampus, two brain areas considered as key regions in the pathogenesis of schizophrenia. In the present study a 3D-T1w MR imaging procedure and an extensive clinical assessment was carried out in 18 patients with schizophrenia, (10 DS and 8 NDS). 3D MPRAGE images were preprocessed with SPM software and two regions of interest (hippocampus and DLPFC) were manually traced to obtain their gray matter volumes. We found a significant reduction of DLPFC in the entire schizophrenia group, with respect to healthy subjects. Although the subgroup of patients with DS had a more severe clinical picture and more impaired social functioning, the DLPFC volume reduction was greater in NDS than in DS patients. In conclusion, according to our structural neuroimaging findings, DS patients, although characterized by a more severe clinical picture and a worse outcome, show less neurobiological abnormalities.