Abnormal Structural Connectivity Patterns in Large-Scale Brain Networks in Schizophrenia

Background: While cognitive impairment is a core feature of schizophrenia, a minority of patients demonstrate average to superior ability on many standard cognitive measures with no attenuation of the psychotic disease process (Heinrichs et al. 2008; Muharib et al., 2014). The data imply a dissociation of cognitive and psychosis-generating neural mechanisms whereby patients share a disease process that leads to psychosis but vary in terms of the pathophysiology that causes cognitive impairment. Furthermore, current views hold that schizophrenia involves abnormalities in the connectivity of large-scale brain networks [default mode (DMN), salience (SN), central executive (CEN), and social brain (SBN)]. However, these findings may reflect pathophysiology related to both the cognitive and psychotic features of schizophrenia. Therefore, we asked: Are aberrations in cortical thickness and/or structural connectivity within and between networks associated with cognitive impairment and/or the severity of psychotic psychopathology? Method: Structural magnetic resonance (MRI) and diffusion tensor imaging (DTI), cognitive, and clinical data were collected from 121 participants, which include 16 cognitively-intact and 48 cognitively-impaired schizophrenia patients as well as 36 cognitively normal and 21 below-normal controls. Between-group comparisons and region-of-interest analyses of cortical thickness and structural integrity in the DMN, SN, CEN, and SBN were performed on MRI and DTI data. Results: Cognitively normal controls had greater DMN and SN cortical thickness than both cognitively normal and below-normal patients. Structural integrity of the genu of the corpus callosum was significantly different between cognitively normal controls and both patient groups. Superior longitudinal fasciculus connectivity patterns differed between cognitively normal controls and below-normal patients. Lastly, the inferior longitudinal and inferior fronto-occipital fasciculi combined were significantly different between cognitively normal controls and patients. Conclusions: The results suggest that cortical thinning may represent the presence of psychotic psychopathology independent of cognitive impairment. However, tract integrity may index cognitive status, the psychotic disease process, or both. The similarities in white matter integrity associations with cognition among cognitively normal patients and controls suggest shared neurocognitive processes, and the dissimilarities may point to cortical structure aberrations that give rise to psychotic psychopathology. Taken together, this study contributes to the advancement of the literature by providing evidence for dissociable or partially dissociable disease processes in psychotic illness

Smoking Status, Cognition, and Neurobiology in Schizophrenia

Cognitive impairments are considered a core feature of schizophrenia. Nicotine has been suggested to have an effect on cognition in individuals with schizophrenia and in the general population. Since smoking status is seldom controlled for in cognitive research studies understanding the contribution of nicotine dependence is a potentially important issue for data interpretation. Thus, the current study examined whether smoking status has a differential association with cognition and regional cortical thickness in 71 patients and 63 nonpsychiatric control participants. Cognition was measured with the MATRICS Consensus Cognitive Battery (MCCB) and social cognition was measured with the Faux Pas and Reading the Mind in the Eye tasks. The Vocabulary and Matrix Reasoning subtests of the Wechsler Abbreviated Scale of Intelligence (WASI) and Wide Range Achievement Test (WRAT-4) were used to assess general intelligence (IQ) and premorbid functioning, respectively. Cortical thickness was measured with a high-resolution 3-Tesla MR whole body scanner. Results revealed that patients (relative to controls) and smokers (as compared to nonsmokers) showed impairments on all cognitive measures (e.g., attention, processing speed, working memory, social cognition, etc.). Neuroimaging results indicated widespread cortical thinning among patients as compared to controls. However, patient smokers and control nonsmokers had similar cortical thickness patterns in the left parahippocampal gyrus and bilateral medial orbitofrontal gyri. The findings suggest that smoking status should be taken into consideration in cognitive research given that smoking status may confound overall results

Nicotine has a Direct Effect on Brainstem Startle-Mediating Neurons

Individuals with schizophrenia have impairments in prepulse inhibition of startle (PPI) which correlates with cognitive deficits. Nicotine improves the performance of patients and healthy individuals with PPI deficits on PPI tests. We hypothesized that nicotine directly affect startle-mediating neurons of the caudal pontine recticular nucleus (PnC) of the brainstem using electrophysiological recordings. The data revealed that nicotine (10 pM) increases leak current amplitude, reduces membrane resistance, and depolarizes the resting membrane potential. Nicotine had no significant effect on the EPSC amplitude for neither the trigeminal nor auditory stimulations. All effects were reversed only by a high dose (10 pM) of the a-j nAChR antagonist MLA and a low dose of TMPH (lOOnM; antagonizes all but the a7 nAChR). The effect of nicotine persisted in the presence of cadmium (100 pM), which blocks synaptic transmission. These results confirm the functional expression of nAChRs in the PnC and suggest a role of nAChRs in modulating startle responses directly in the brainstem

Abnormal Structural Connectivity Patterns in Large-Scale Brain Networks in Schizophrenia

Background: While cognitive impairment is a core feature of schizophrenia, a minority of patients demonstrate average to superior ability on many standard cognitive measures with no attenuation of the psychotic disease process (Heinrichs et al. 2008; Muharib et al., 2014). The data imply a dissociation of cognitive and psychosis-generating neural mechanisms whereby patients share a disease process that leads to psychosis but vary in terms of the pathophysiology that causes cognitive impairment. Furthermore, current views hold that schizophrenia involves abnormalities in the connectivity of large-scale brain networks [default mode (DMN), salience (SN), central executive (CEN), and social brain (SBN)]. However, these findings may reflect pathophysiology related to both the cognitive and psychotic features of schizophrenia. Therefore, we asked: Are aberrations in cortical thickness and/or structural connectivity within and between networks associated with cognitive impairment and/or the severity of psychotic psychopathology? Method: Structural magnetic resonance (MRI) and diffusion tensor imaging (DTI), cognitive, and clinical data were collected from 121 participants, which include 16 cognitively-intact and 48 cognitively-impaired schizophrenia patients as well as 36 cognitively normal and 21 below-normal controls. Between-group comparisons and region-of-interest analyses of cortical thickness and structural integrity in the DMN, SN, CEN, and SBN were performed on MRI and DTI data. Results: Cognitively normal controls had greater DMN and SN cortical thickness than both cognitively normal and below-normal patients. Structural integrity of the genu of the corpus callosum was significantly different between cognitively normal controls and both patient groups. Superior longitudinal fasciculus connectivity patterns differed between cognitively normal controls and below-normal patients. Lastly, the inferior longitudinal and inferior fronto-occipital fasciculi combined were significantly different between cognitively normal controls and patients. Conclusions: The results suggest that cortical thinning may represent the presence of psychotic psychopathology independent of cognitive impairment. However, tract integrity may index cognitive status, the psychotic disease process, or both. The similarities in white matter integrity associations with cognition among cognitively normal patients and controls suggest shared neurocognitive processes, and the dissimilarities may point to cortical structure aberrations that give rise to psychotic psychopathology. Taken together, this study contributes to the advancement of the literature by providing evidence for dissociable or partially dissociable disease processes in psychotic illness

Cortical Thinning in Network-Associated Regions in Cognitively Normal and Below-Normal Range Schizophrenia

This study assessed whether cortical thickness across the brain and regionally in terms of the default mode, salience, and central executive networks differentiates schizophrenia patients and healthy controls with normal range or below-normal range cognitive performance. Cognitive normality was defined using the MATRICS Consensus Cognitive Battery (MCCB) composite score (T=50 ± 10) and structural magnetic resonance imaging was used to generate cortical thickness data. Whole brain analysis revealed that cognitively normal range controls (n=39) had greater cortical thickness than both cognitively normal (n=17) and below-normal range (n=49) patients. Cognitively normal controls also demonstrated greater thickness than patients in regions associated with the default mode and salience, but not central executive networks. No differences on any thickness measure were found between cognitively normal range and below-normal range controls (n=24) or between cognitively normal and below-normal range patients. In addition, structural covariance between network regions was high and similar across subgroups. Positive and negative symptom severity did not correlate with thickness values. Cortical thinning across the brain and regionally in relation to the default and salience networks may index shared aspects of the psychotic psychopathology that defines schizophrenia with no relation to cognitive impairment