Background Processing speed predicts functional outcome and is a potential endophenotype for schizophrenia. Establishing the neural basis of processing speed impairment may inform the treatment and etiology of schizophrenia. Neuroimaging investigations in healthy subjects have linked processing speed to brain anatomical connectivity. However, the relationship between processing speed impairment and white matter integrity in schizophrenia is unclear. Methods Individuals with schizophrenia and healthy subjects underwent diffusion tensor imaging (DTI) and completed a brief neuropsychological assessment that included measures of processing speed, verbal learning, working memory, and executive functioning. Group differences in white matter integrity, inferred from fractional anisotropy (FA), were examined throughout the brain and the hypothesis that processing speed impairment in schizophrenia is mediated by diminished white matter integrity was tested. Results White matter integrity of the corpus callosum, cingulum, superior and inferior frontal gyri, and precuneus was reduced in schizophrenia. Average FA in these regions mediated group differences in processing speed, but not other cognitive domains. Diminished white matter integrity in schizophrenia was accounted for, in large part, by individual differences in processing speed. Conclusions Cognitive impairment in schizophrenia mediated by reduced white matter integrity. This relationship was strongest for processing speed as deficits in working memory, verbal learning, and executive functioning were not mediated by white integrity. Larger sample sizes may be required to detect more subtle mediation effects in these domains. Interventions that preserve white matter integrity or ameliorate white matter disruption may enhance processing speed and functional outcome in schizophrenia.

Processing speed is the most impaired neuropsychological domain in schizophrenia and a robust predictor of functional outcome. Determining the specific cognitive operations underlying processing speed dysfunction and indentifying their neural correlates may assist in developing pro-cognitive interventions. Response selection, the process of mapping stimuli onto motor responses, correlates with neuropsychological tests of processing speed and may contribute to processing speed impairment in schizophrenia. This study investigated the relationship between behavioral and neural measures of response selection, and a neuropsychological index of processing speed in schizophrenia. 26 patients with schizophrenia and 21 healthy subjects underwent fMRI scanning during performance of 2 and 4-choice-reaction time (RT) tasks and completed the Wechsler Adult Intelligence Scale-III (WAIS) Processing Speed Index (PSI). Response selection, defined as RT slowing between 2 and 4-choice RT, was impaired in schizophrenia and correlated with psychometric processing speed. Greater activation of the dorsolateral prefrontal cortex (PFC) was observed in schizophrenia and correlated with poorer WAIS PSI scores. Deficient response selection and abnormal recruitment of the dorsolateral PFC during response selection contribute to processing speed impairment in schizophrenia. Interventions that improve response selection and normalize dorsolateral PFC function may improve processing speed in schizophrenia.

Response selection dysfunction contributes to processing speed impairment in schizophrenia. However, it is unclear if response selection impairment transcends sensory and motor modalities or is modality specific. To address this question, healthy subjects and individuals with schizophrenia completed reaction time (RT) experiments with different combinations of sensory cues (i.e. visual, auditory) and motor response (i.e. manual, vocal). We found that response selection impairment in schizophrenia was present regardless of the sensory and motor modality of the tasks and correlated with performance on neuropsychological tests of processing speed. These results implicate dysfunction of amodal response selection brain regions in schizophrenia. Interventions that reduce the length of response selection stage processing may improve processing speed in schizophrenia.

The long-term effects of mild TBI (mTBI) are not well understood, and there is an ongoing debate about whether there are sex differences in outcomes following mTBI. This study examined i) symptom burden and functional outcomes at 8-years post-injury in males and females following mTBI; ii) sex differences in outcomes at 8-years post-injury for those aged <45 years and ≥45 years and; iii) sex differences in outcomes for single and repetitive TBI. Adults (≥16 years at injury) identified as part of a population-based TBI incidence study (BIONIC) who experienced mTBI 8-years ago (N = 151) and a TBI-free sample (N = 151) completed self-report measures of symptoms and symptom burden (Rivermead Post-Concussion Symptom Questionnaire, Hospital Anxiety and Depression Scale, Post-traumatic Stress Disorder Checklist), and functional outcomes (Participation Assessments with Recombined Tools, Work Limitations Questionnaire). The mTBI group reported significantly greater post-concussion symptoms compared to the TBI-free group (F(1,298) = 26.84, p<.01, ηp2 = .08). Females with mTBI were twice as likely to exceed clinical cut-offs for post-concussive (X2 (1)>5.2, p<.05, V>.19) and PTSD symptoms (X2(1) = 6.10, p = .014, V = .20) compared to the other groups, and reported their health had the greatest impact on time-related work demands (F(1,171) = 4.36, p = .04, ηp2 = .03. There was no interaction between sex and age on outcomes. The repetitive mTBI group reported significantly greater post-concussion symptoms (F(1,147) = 9.80, p<.01, ηp2 = .06) compared to the single mTBI group. Twice the proportion of women with repetitive mTBI exceeded the clinical cut-offs for post-concussive (X2(1)>6.90, p<.01, V>.30), anxiety (X2(1)>3.95, p<.05, V>.23) and PTSD symptoms (X2(1)>5.11, p<.02, V>.26) compared with males with repetitive TBI or women with single TBI. Thus, at 8-years post-mTBI, people continued to report a high symptom burden. Women with mTBI, particularly those with a history of repetitive mTBI, had the greatest symptom burden and were most likely to have symptoms of clinical significance. When treating mTBI it is important to assess TBI history, particularly in women. This may help identify those at greatest risk of poor long-term outcomes to direct early treatment and intervention.