Clinical outcomes vary among youths at clinical high risk for psychosis (CHR-P), with approximately 20% progressing to full-blown psychosis over 2 to 3 years and 30% achieving remission. Recent ...research efforts have focused on identifying biomarkers that precede psychosis onset and enhance the accuracy of clinical outcome prediction in CHR-P individuals, with the ultimate goal of developing staged treatment approaches based on the individual’s level of risk. Identifying such biomarkers may also facilitate progress toward understanding pathogenic mechanisms underlying psychosis onset, which may support the development of mechanistically informed early interventions for psychosis. In recent years, electroencephalography-based event-related potential measures with established sensitivity to schizophrenia have gained traction in the study of CHR-P and its clinical outcomes. In this review, we describe the evidence for event-related potential abnormalities in CHR-P and discuss how they inform our understanding of information processing deficits as vulnerability markers for emerging psychosis and as indicators of future outcomes. Among the measures studied, P300 and mismatch negativity are notable because deficits predict conversion to psychosis and/or CHR-P remission. However, the accuracy with which these and other measures predict outcomes in CHR-P has been obscured in the prior literature by the tendency to only report group-level differences, underscoring the need for inclusion of individual predictive accuracy metrics in future studies. Nevertheless, both P300 and mismatch negativity show promise as electrophysiological markers of risk for psychosis, as target engagement measures for clinical trials, and as potential translational bridges between human studies and animal models focused on novel drug development for early psychosis.
Reduced thalamic volume is consistently observed in schizophrenia, and correlates with cognitive impairment. Targeted cognitive training (TCT) of auditory processing in schizophrenia drives ...improvements in cognition that are believed to result from functional neuroplasticity in prefrontal and auditory cortices. In this study, we sought to determine whether response to TCT is also associated with structural neuroplastic changes in thalamic volume in patients with early schizophrenia (ESZ). Additionally, we examined baseline clinical, cognitive, and neural characteristics predictive of a positive response to TCT. ESZ patients were randomly assigned to undergo either 40 h of TCT (N=22) or a computer games control condition (CG; N=22 s). Participants underwent MRI, clinical, and neurocognitive assessments before and after training (4-month interval). Freesurfer automated segmentation of the subcortical surface was carried out to measure thalamic volume at both time points. Left thalamic volume at baseline correlated with baseline global cognition, while a similar trend was observed in the right thalamus. The relationship between change in cognition and change in left thalamus volume differed between groups, with a significant positive correlation in the TCT group and a negative trend in the CG group. Lower baseline symptoms were related to improvements in cognition and left thalamic volume preservation following TCT. These findings suggest that the cognitive gains induced by TCT in ESZ are associated with structural neuroplasticity in the thalamus. Greater symptom severity at baseline reduced the likelihood of response to TCT both with respect to improved cognition and change in thalamic volume.
Psychotic-like experiences (PLEs) may reflect elevated risk for serious mental illness, including psychosis. Although some studies report an association between PLEs and increased service ...utilization, there is evidence of unmet need among individuals with PLEs, with few studies exploring the relation between PLEs and intent to seek treatment. Characterizing factors that underlie intent to seek treatment in individuals not otherwise engaged in treatment may assist in determining the role of PLEs and future intentions, and help prioritize symptoms of greatest significance. Non-help-seeking participants ages 16-30 years (n
= 2529) in a multi-site study completed online questionnaires of PLEs (PRIME with distress), depression (CESD), anxiety (STAI), and intention to seek mental health treatment. Associations between PLEs and intent to seek treatment were analyzed through multiple linear regressions. PRIME scores predicted intent to seek treatment, and item-level analyses suggested that this association was driven by items 12 ("going crazy"), 7 (wondering if people may hurt me), 5 (confused if things are real or imagination/dreams), and 1 (odd/unusual things going on). When accounting for the effects of anxiety and depression, PLE sum scores as well as individual experiences remained statistically significant, although effect sizes were negligible. Findings suggest that PLEs can play a role in identifying individuals who intend to seek mental health services and warrant further research in independent samples.
•Response to cognitive training coincided with changes in cortical thickness.•Change in cortical thickness correlated across regions following training.•Cortical thickness changes mediated thalamic ...volume and global cognition relationships.
Individuals with schizophrenia exhibit widespread cortical thinning associated with illness severity and deficits in cognition. However, intact cortical thickness (CTh) may serve as a protective factor. The current study sought to examine changes in CTh in response to auditory targeted cognitive training (TCT) in individuals with recent onset schizophrenia. Participants underwent MRI scanning and a cognitive assessment before and after being randomly assigned to 40 h of either TCT (N = 21) or a computer games control condition (CG; N = 22) over 16 weeks. Groups did not differ at baseline on demographic variables or measures of CTh. At the level of group averages, neither group showed significant pre-post changes in CTh in any brain region. However, changes in CTh related to individual differences in treatment outcome, as improved global cognition in the TCT group corresponded to reduced cortical thinning in frontal, temporal, parietal, and occipital lobes. These relationships were not observed in the CG group. The current findings suggest that TCT may be neuroprotective in early schizophrenia, such that individuals who improved in response to training also showed a reduction in cortical thinning that may be otherwise hastened due to age and illness.
Abstract
Background
Targeted cognitive training (TCT) for schizophrenia is hypothesized to improve global cognitive functioning by driving plasticity in distributed frontal and temporal systems. ...While previous work has demonstrated that TCT evokes functional changes in prefrontal and temporal cortex, less is known about whether treatment response coincides with structural changes in these brain areas. In the current study, we examined whether changes in cognition in response to TCT (compared to a computer games control condition) correspond to changes in cortical thickness (CTh) in frontal and temporal cortices among patients with recent onset schizophrenia (SZ). Additionally, we determined whether baseline CTh predicted treatment response.
Methods
SZ patients were randomized to 40 hours of TCT of the auditory system (N=21) or computer games (CG; N=22). Before and after training, participants underwent MRI and cognitive testing. Freesurfer’s longitudinal pipeline was used to calculate CTh at baseline and follow up. Patients averaged 4.5 months to complete training. Using regions from the Desikan-Killiany Atlas, we created regions of interest (ROIs) from left and right frontal and temporal cortices and calculated CTh change scores. Next, we examined slope differences to determine whether the relationship between change in CTh and change in cognition differed between TCT and CG. Last, we determined whether baseline CTh in any sub-regions of the ROIs was predictive of treatment response in the TCT group.
Results
The relationship between change in CTh and global cognition differed between groups in the left frontal cortex (t=2.42; p=.02), characterized by a correlation in TCT (r=.50 p=.02), but no relationship in CG (r=-.18; p=.42). The same pattern was observed in the right frontal cortex (t=3.29 p=.002; TCT: r=.59; p=.004; CG: r=-.29 p=.18). We observed a similar pattern in the temporal cortex, with a significant slope difference in the left hemisphere (t=2.38 p=.02), characterized by a correlation in TCT (r=.58 p=.006) but not CG (r=-.13 p=.55). The same trend was observed in the right temporal cortex (t=1.93 p=.06), with a strong TCT correlation (r=.72 p=.0002), and no relationship in CG (r=.11 p=.61). We observed no significant group x time interactions on change in CTh. We conducted post-hoc analyses on sub-region ROIs that may be driving these relationships and identified numerous frontal and temporal regions showing a significant slope difference, including superior and middle frontal gyrus, as well as temporal pole, inferior, and middle temporal regions (all p’s<.05 – uncorrected). Finally, we investigated whether CTh in sub-region ROIs at baseline predicted response to treatment. The right caudal middle frontal gyrus (r=-.45, p=.04 - uncorrected), the left entorhinal cortex (r=-.57, p=.007 - uncorrected), and right inferior temporal gyrus (r=-.62, p=.003 - uncorrected), all showed lower baseline CTh relating to gains in global cognition.
Discussion
The current results demonstrate that response to TCT in recent onset SZ coincides with changes in CTh in both the frontal and temporal lobes. These changes appear to be driven by neuroplasticity in regions critical for auditory processing and cognitive control. Taken with related research, these findings support the hypothesis that TCT of the auditory system influences cognition by way of coordinated plasticity in distributed temporal and prefrontal regions. Additionally, we demonstrate that lower CTh in sub-lobar frontal and temporal ROIs corresponds to greater subsequent gains in cognition, suggesting that SZ patients with greater pathophysiological impairments may be especially responsive to targeted training interventions.
Background:
Thalamic volume loss in schizophrenia has been consistently observed both early in, and throughout, the illness’ course. Thalamic volume reduction is hypothesized to relate to aspects of ...symptomology, illness chronicity, and the effects of pharmacological treatments. Notably, volume loss has been found to correspond to changes in measures of complex and speeded cognitive processing, both over the course of the healthy adult life span as well as in schizophrenia. Interventions such as targeted cognitive training (TCT) have been observed to improve cognitive functioning and outcome in schizophrenia, but may also be protective against the dysplastic effects of the illness. The current study examined whether response to TCT is neuroprotective against thalamic volume loss in early schizophrenia (ESZ). Additionally, we sought to identify baseline clinical and neural characteristics predictive of response to TCT.
Methods:
ESZ patients were randomly assigned to undergo either 40 hours of remotely delivered TCT (N = 22), or a computer games (CG; N = 22s) control. Participants underwent MRI, clinical, and neurocognitive assessments before and after training. Participants took on average 4.5 months to complete training. Freesurfer automated segmentation of the subcortical surface was carried out to identify thalamic volume at both time points.
Results:
Left thalamus volume at baseline correlated with baseline neurocognition (
r
= .62;
P
= .04), while a similar trend was observed in the right thalamus (
r
= .25;
P
= .10). Increases in left thalamic volume significantly correlated with improvements in neurocognitive scores following TCT (
r
= .62;
P
= .002), while the opposite effect was observed following the CG condition (
r
= −.41;
P
= .06). Additionally, the difference in slopes between the groups was significant (
P
= .0004). Finally, lower baseline PANSS scores were related to response to TCT both on measures of neurocognition (
r
= −.38;
P
= .08) and left thalamic volume preservation (
r
= −.45;
P
= .04). Baseline thalamic volume was not predictive of changes in neurocognition or thalamic preservation. Similar, though attenuated, patterns were observed in the right thalamus.
Conclusion:
Neurocognitive improvements in response to TCT were found to be neuroprotective against thalamic volume reduction in individuals with ESZ. These effects were not observed in the control condition. Additionally, individuals with greater illness severity at baseline were less likely to respond to TCT both with respect to improved neurocognition and protection against thalamic volume loss. These findings offer a plausible mechanism by which TCT may be protective against the dysplastic effects of schizophrenia.
Background and Objectives. Cardiovascular disease (CVD) is a leading cause of death among military veterans with several reports suggesting a link between combat and related traumatic injury (TI) to ...an increased CVD risk. The aim of this paper is to conduct a widespread systematic review and meta-analysis of the relationship between military combat ± TI to CVD and its associated risk factors. Methods. PubMed, EmbaseProQuest, Cinahl databases and Cochrane Reviews were examined for all published observational studies (any language) reporting on CVD risk and outcomes, following military combat exposure ± TI versus a comparative nonexposed control population. Two investigators independently extracted data. Data quality was rated and rated using the 20-item AXIS Critical Appraisal Tool. The risk of bias (ROB using the ROBANS 6 item tool) and strength of evidence (SOE) were also critically appraised. Results. From 4499 citations, 26 studies (14 cross sectional and 12 cohort; 78–100% male) met the inclusion criteria. The follow up period ranged from 1 to 43.6 years with a sample size ranging from 19 to 621901 participants in the combat group. Combat-related TI was associated with a significantly increased risk for CVD (RR 1.80: 95% CI 1.24–2.62; I 2 = 59 % , p = 0.002 ) and coronary heart disease (CHD)-related death (risk ratio 1.57: 95% CI 1.35–1.83; I 2 = 0 % , p = 0.77 : p < 0.0001 ), although the SOE was low. Military combat (without TI) was linked to a marginal, yet significantly lower pooled risk (low SOE) of cardiovascular death in the active combat versus control population (RR 0.90: CI 0.83–0.98; I 2 = 47 % , p = 0.02 ). There was insufficient evidence linking combat ± TI to any other cardiovascular outcomes or risk factors. Conclusion. There is low SOE to support a link between combat-related TI and both cardiovascular and CHD-related mortality. There is insufficient evidence to support a positive association between military combat ± any other adverse cardiovascular outcomes or risk factors. Data from well conducted prospective cohort studies following combat are needed.
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