Dopamine abnormalities in the neocortex of patients with temporal lobe epilepsy

Experiments were designed to evaluate different variables of the dopaminergic system in the temporal cortex of surgically treated patients with temporal lobe epilepsy (TLE) associated with mesial sclerosis (MTLE, n = 12) or with cerebral tumor or lesion (n = 8). In addition, we sought to identify dopaminergic abnormalities in those patients with epilepsy that had comorbid anxiety and depression. Specifically, we investigated changes in dopamine and its metabolites, D1 and D2 receptors, tyrosine hydroxylase (TH) and dopamine transporter. Results obtained from patients with epilepsy were compared with those found in experiments using autopsy material. The neocortex of patients with MTLE demonstrated high D1 expression (1680%, p < 0.05) and binding (layers I-II, 31%, p < 0.05; layers V-VI, 28%, p < 0.05), and decreased D2 expression (77%, p < 0.05). The neocortex of patients with TLE secondary to cerebral tumor or lesion showed high expression of D1 receptors (1100%, p < 0.05), and D2-like induced activation of G proteins (layers I-II, 503%; layers III-IV, 557%; layers V-VI, 964%, p < 0.05). Both epileptic groups presented elevated binding to the dopamine transporter and low tissue content of dopamine and its metabolites. Analysis revealed the following correlations: a) D1 receptor binding correlated negatively with seizure onset age and seizure frequency, and positively with duration of epilepsy; b) D2 receptor binding correlated positively with age of seizure onset and negatively with duration of epilepsy; c) dopamine transporter binding correlated positively with duration of epilepsy and frequency of seizures; d) D2-like induced activation of G proteins correlated positively with the age of patients. When compared with autopsies and patients with anxiety and depression, patients without neuropsychiatric disorders showed high D2-like induced activation of G proteins, an effect that correlated positively with age of patient and seizure onset age, and negatively with duration of epilepsy. The present study suggests that alterations of the dopaminergic system result from epileptic activity and could be involved in the physiopathology of TLE and the comorbid anxiety and depression.     

Saccadic eye movement abnormalities in relatives of patients with schizophrenia

Recent studies note abnormalities in saccadic eye movements of relatives of patients with schizophrenia. The current study examined which aspects of the saccadic system are affected, whether these saccadic abnormalities are associated with schizophrenia spectrum personality symptoms (SSP), and whether such an association is dependent on a family history of schizophrenia. Furthermore, the study examined what proportion of relatives have the saccadic abnormality(ies). Fifty-five first-degree relatives with no DSM-III-R Axis I diagnosis participated in the study. Twenty-one of these relatives experienced SSP symptoms and 34 had no Axis II diagnosis. Sixty-two subjects with no Axis I diagnosis were recruited from the community. Twenty-five experienced SSP symptoms and 37 had no Axis II diagnosis. Prosaccades (saccades toward the target) and antisaccades (saccades made in the opposite direction of the target jump) were examined. Relatives, particularly those with SSP, had difficulties with the antisaccade task as suggested by higher error rates and longer antisaccade latency. Prosaccades were not different in relatives compared to the community subjects, although the effects of field were different in the two groups on some measures. The antisaccade latency was 'abnormal' in only a small proportion (1.6%) of community subjects compared to 14.9% of all relatives (35.3% of SSP relatives and 3.3% of non-SSP relatives). Relatives of patients with schizophrenia have deficits in aspects of the saccadic system involved in generating internally driven saccades and inhibition of unwanted saccades. These deficits implicate frontal ocular motor neuronal circuitry involving frontal cortical and basal ganglia areas. These deficits are associated with SSP symptoms, but not in the absence of a blood relationship to schizophrenia. The relatively high prevalence rate of the abnormality in at-risk subjects may have relevance for use of these measures in linkage analysis.     

Proactive response inhibition abnormalities in the sensorimotor cortex of patients with schizophrenia

BackgroundPrevious studies of response inhibition in patients with schizophrenia have focused on reactive inhibition tasks (e.g., stop-signal, go/no-go), primarily observing lateral prefrontal cortex abnormalities. However, recent studies suggest that purposeful and sustained (i.e., proactive) inhibition may also be affected in these patients.MethodsPatients with chronic schizophrenia and healthy controls underwent fMRI while inhibiting motor responses during multisensory (audiovisual) stimulation. Resting state data were also collected.ResultsWe included 37 patients with schizophrenia and 37 healthy controls in our study. Both controls and patients with schizophrenia successfully inhibited the majority of overt motor responses. Functional results indicated basic inhibitory failure in the lateral premotor and sensorimotor cortex, with opposing patterns of positive (schizophrenia) versus negative (control) activation. Abnormal activity was associated with independently assessed signs of psychomotor retardation. Patients with schizophrenia also exhibited unique activation of the pre–supplementary motor area (pre-SMA)/SMA and precuneus relative to baseline as well as a failure to deactivate anterior nodes of the default mode network. Independent resting-state connectivity analysis indicated reduced connectivity between anterior (task results) and posterior regions of the sensorimotor cortex for patients as well as abnormal connectivity between other regions (cerebellum, thalamus, posterior cingulate gyrus and visual cortex).LimitationsAside from rates of false-positive responses, true proactive response inhibition tasks do not provide behavioural metrics that can be independently used to quantify task performance.ConclusionOur results suggest that basic cortico-cortico and intracortical connections between the sensorimotor cortex and adjoining regions are impaired in patients with schizophrenia and that these impaired connections contribute to inhibitory failures (i.e., a positive rather than negative hemodynamic response).     

Volumetric abnormalities in connectivity-based subregions of the thalamus in patients with chronic schizophrenia

OBJECTIVE: The thalamus, which consists of multiple subnuclei, has been of particular interest in the study of schizophrenia. This study aimed to identify abnormalities in the connectivity-based subregions of the thalamus in patients with schizophrenia. METHODS: Thalamic volume was measured by a manual tracing on superimposed images of T1-weighted and diffusion tensor images in 30 patients with schizophrenia and 22 normal volunteers. Cortical regional volumes automatically measured by a surface-based approach and thalamic subregional volumes measured by a connectivity-based technique were compared between the two groups and their correlations between the connected regions were calculated in each group. RESULTS: Volume reduction was observed in the bilateral orbitofrontal cortices and the left cingulate gyrus on the cortical side, whereas in subregions connected to the right orbitofrontal cortex and bilateral parietal cortices on the thalamic side. Significant volumetric correlations were identified between the right dorsal prefrontal cortex and its related thalamic subregion and between the left parietal cortex and its related thalamic subregion only in the normal group. CONCLUSIONS: Our results suggest that patients with schizophrenia have a structural deficit in the corticothalamic systems, especially in the orbitofrontal-thalamic system. Our findings may present evidence of corticothalamic connection problems in schizophrenia.     

Structural brain abnormalities in patients with schizophrenia and their healthy siblings

OBJECTIVE: The authors sought to investigate the contribution of genotype on structural brain abnormalities in schizophrenia. METHOD: Intracranial volumes and volumes of the cerebrum, white and gray matter, lateral and third ventricles, frontal lobes, caudate nucleus, amygdala, hippocampus, parahippocampal gyrus, and the cerebellum were measured in 32 same-sex siblings discordant for schizophrenia and 32 matched comparison subjects by means of magnetic resonance imaging. RESULTS: Third ventricle volumes did not differ between the schizophrenic patients and their healthy siblings. However, both had higher third ventricle volumes than did the comparison subjects. The schizophrenic patients had lower cerebrum volumes than did the comparison subjects, whereas the cerebrum volume of the healthy siblings did not significantly differ from the patients or comparison subjects. Additionally, patients with schizophrenia displayed a volume reduction of the frontal lobe gray matter and a volume increase of the caudate nuclei and lateral ventricles compared to both their healthy siblings and comparison subjects. Intracranial volume, CSF volume, or volumes of the cerebellum, amygdala, hippocampus, or the parahippocampal gyrus did not significantly differ among the patients, siblings, and comparison subjects. CONCLUSIONS: Healthy siblings share third ventricle enlargement with their affected relatives and may partially display a reduction in cerebral volume. These findings suggest that third ventricular enlargement, and to some extent cerebral volume decrease, may be related to genetic defects that produce a susceptibility to schizophrenia.     

Ultrastructural damage of capillaries in the neocortex in schizophrenia

Abstract

Objectives. Neuroimaging studies showed lowered blood flow, glucose metabolic rates and hypoactivation of the prefrontal cortex (PFC) in patients with schizophrenia. The aim of the study was to clear up whether there are abnormalities in the microvasculature in the neocortex in schizophrenia. Methods. Capillaries were studied in PFC (BA 10) and visual cortex (VC) (BA 17) by electron microscopy and morphometry in 26 schizophrenia cases and 26 normal controls. Capillary diameter and areas of capillaries and of pericapillary astrocytic end-feet were estimated in layers I–II of the prefrontal and visual cortices. Results. Ultrastructural abnormalities of capillaries in schizophrenia included thickening, deformation of basal lamina, vacuolation of cytoplasm of endothelial cells, basal lamina and astrocytic end-feet, swelling of astrocytic end-feet, of pericapillary oligodendrocytes and signs of activation of microglial cells in both PFC and VC. Capillary diameter and area did not differ significantly between the groups. Area of astrocytic end-feet was significantly higher in PFC (+49%, P<0.001) and in VC (+29%, P<0.01) in schizophrenic group and in different clinical subgroups as compared to controls. Conclusions. Ultrastructural abnormalities of capillaries and of pericapillary cellular environment found suggest that blood-brain barrier dysfunction might contribute to the pathogenesis of cortical lesions in schizophrenia.     

N400 and automatic semantic processing abnormalities in patients with schizophrenia

BACKGROUND: One factor hypothesized to underlie thinking disturbance in patients with schizophrenia is abnormal or disinhibited automatic spreading activation of semantic networks, which can be assessed using the N400 event-related potential. N400 is a negative-going component elicited at about 400 milliseconds following semantic stimuli that are not primed by the preceding context. Semantic priming refers to facilitated semantic processing gained through preexposure to semantic context, which can happen automatically or strategically. Using N400, inferences can be drawn regarding the extent to which a given context primes a word. METHODS: During a picture-word matching task, N400s to primed (exact match) and unprimed (remotely related) words were recorded from 18 healthy control subjects and 18 patients with schizophrenia performing a picture-word matching task. A short interval (325 milliseconds) between picture and word onset (stimulus-onset asynchrony) was used to optimize the role of automatic spreading semantic activation and to minimize the role of attention, expectancy, preparation, and working memory. RESULTS: Despite behavioral evidence of normal semantic priming, patients generated an abnormally small N400 (ie, less negative) to unprimed words. The N400 to primed words was neither larger nor smaller in patients than in controls, suggesting normal use of context. CONCLUSIONS: A reduced N400 to unprimed words in patients with schizophrenia suggests that there was inappropriate priming of words by remotely related semantic contexts. This is consistent with an overly broad automatic spread of activation through semantic networks in patients with schizophrenia.     

精神分裂症患者脑结构异常的MRI研究

目的　探讨脑结构的改变 (尤其是第Ⅲ脑室 )特点及其与精神分裂症症状产生及疗效的关系。方法　选用我院住院的首发精神分裂症患者 ,共 51例 ,正常对照组为 2 3例健康志愿者。对入组后的患者于治疗前和治疗后 2个月进行PANSS(阳性与阴性症状量表 )评定 ,以PANSS减分率作为疗效指标。磁共振成像扫描采用SiemensMagnetomP8型永磁性磁共振机 ,磁场强度 0 2T。测量包括第Ⅲ脑室横径等在内的 1 7条径线。结果　病例组第Ⅲ脑室横径、双侧外侧裂宽度明显增宽 ,胼胝体厚度明显减少 ,病例组与对照组之间存在显著差异。PANSS阴性分量表、思维解体因子减分率与左侧海马横径均呈负相关。PANSS其他分量表及因子减分率与MRI各参数均无显著相关。结论　精神分裂症患者存在的脑结构异常可能构成了精神分裂症的神经生物学基础。脑结构异常与疗效的关系有待进一步研究     

Brain response abnormalities during verbal learning among patients with schizophrenia

Patients with schizophrenia often show verbal learning deficits that have been linked to the pathophysiology of the disorder and result in functional impairment. This study examined the biological basis of these deficits by comparing the brain response of patients with schizophrenia (n=17) to that of healthy comparison participants (n=14) during a verbal paired-associates learning task using functional magnetic resonance imaging (fMRI). Brain response during new word learning was examined within and between groups in two a priori regions of interest, the inferior frontal gyrus and hippocampus, and across the whole brain. In regions of group difference, we also examined the relationship of brain response during learning to later recall of the word pairs. Despite successful matching of levels of word-pair recall, patients' brain response during new learning was abnormal in bilateral regions within the inferior frontal gyrus, a small region in left posterior hippocampus, and other areas within the frontal, parietal and temporal cortex compared with healthy individuals. In some regions, but not in the hippocampus, patients with the most normal brain response also remembered the most word pairs following scanning. Thus, verbal learning deficits found among patients with schizophrenia appear to be related to hypofunction of distributed brain networks.     

Structural brain MRI abnormalities in healthy siblings of patients with childhood-onset schizophrenia

OBJECTIVE: Childhood-onset schizophrenia shows progressive brain magnetic resonance imaging (MRI) changes during adolescence, which follow a back-to-front "wave." The authors' goal was to examine whether healthy siblings of patients with childhood-onset schizophrenia show structural brain abnormalities and the age-related pattern of abnormalities seen in patients with childhood-onset schizophrenia. METHOD: Anatomic brain MRI scans were obtained from 15 psychiatrically healthy full siblings of 15 patients with childhood-onset schizophrenia and from 32 matched community volunteers. Automated measures were used to compare total and regional brain volumes of the siblings and volunteers. RESULTS: Siblings of patients with childhood-onset schizophrenia had smaller total cerebral volume and total, frontal, and parietal gray matter volumes than volunteers. When divided into younger and older groups, younger siblings had smaller parietal gray matter volumes and older siblings showed trends for smaller total and frontal gray matter volumes. CONCLUSIONS: Healthy siblings of patients with childhood-onset schizophrenia share brain MRI abnormalities with the patients that may follow a similar pattern of progression. Developmental brain abnormalities in childhood-onset schizophrenia may thus be genetic trait markers.     

Glucose abnormalities in the siblings of people with schizophrenia

BACKGROUND: Some studies suggest that schizophrenia may be associated with an increased risk of diabetes, independently of antipsychotic medications and other confounding factors. Previous studies have also suggested that there is an increased prevalence of diabetes in the relatives of schizophrenia probands. METHOD: First-degree siblings of schizophrenia probands (N=6) and control subjects (N=12) were administered a glucose tolerance test. Subjects were matched for gender, age, body mass index, neighborhood of residence, socio-economic status and smoking habits. RESULTS: The siblings of schizophrenia probands had a significantly increased two-hour mean glucose concentration compared to the control subjects (respective means [SD] were 100.5 mg/dL [27.7] vs. 78.0 [12.3]; p<0.03). Baseline glucose concentrations did not differ. CONCLUSIONS: Although confirmation with larger samples is needed, these results and other studies suggest that diabetes may share familial risk factors with schizophrenia.     

Neuromuscular and psychomotor abnormalities in patients with schizophrenia and their first-degree relatives

In previous studies of schizophrenic patients, neuromuscular (histopathological and electrophysiological) and psychomotor (finger tapping) abnormalities were found. The present study was designed to investigate relationships between these abnormalities and a family history of psychosis in 14 schizophrenic patients and 25 unaffected first-degree relatives compared to 14 healthy controls. Muscle biopsies were performed in either m. tibialis anterior or m. lateralis. Macro EMG recordings were made from m. tibialis anterior. A finger tapping test was used to investigate psychomotor performance. Neuromuscular abnormalities (muscle biopsies and/or macro EMG) and/or aberrant psychomotor performance (finger tapping test) were found in 13 (93%) patients, 14 (56%) first-degree relatives and in three (21%) controls. A statistically significant relationship for the psychomotor, but not neuromuscular changes to a family history of psychosis was found using a logistic regression method. The percentage of patients, relatives and healthy controls exhibiting were 36/40/7% in the muscle biopsy, 50/20/0% in the macro EMG, and 71/82/14% in the finger tapping investigations. A higher frequency of neuromuscular and psychomotor abnormalities was found in patients with schizophrenia and their first-degree relatives compared to healthy controls. The relationship between psychomotor findings and a family history of psychosis indicate that central aspects of motor aberrations are associated with a hereditary disposition of psychosis. The neuromuscular as well as psychomotor changes indicate that schizophrenia may be a systemic disease involving the central nervous system as well as peripheral organs. An altered cell membrane is suggested to be an underlying factor based on the type of neuromuscular findings.     

Relationship between structural brain abnormalities and psychopathologic profile in patients with schizophrenia

Aim of this study was to determine the presence of structural brain abnormalities, dynamics of psychopathology three and seven years after the first hospitalisation and correlation between them. We examined 59 first admitted schizophrenic patients. We used computed tomography to examine structural brain abnormalities and BPRS-LA to measure the psychopathology level. CT and BPRS measures were both completed 3 years after the first admission. 7 years after the first admission the psychopathology level was measured with BPRS. We observed spaces in the brain and cortical sulci widened in 55 subjects (93%). The most commonly met structural brain pathology was a widening of the IIIrd ventricle and frontal cortex pathology. Assessment of the dynamics of psychopathology shows stability of the negative syndrome and increase of the positive syndrome and general psychopathology between the third and the seventh year of the illness. Three years after first admission, structural brain pathology in the left temporal cortex and frontal cortex correlate with the overall level of psychopathology measured with BPRS-LA, but this correlation vanishes in seventh-year catch-up. Seven years after first admission subcortical cerebral pathology, especially in the subcortical frontal area correlate significantly (p < 0.01) with a lower level of positive symptoms.     

Thalamic abnormalities in patients with schizophrenia revealed by proton magnetic resonance spectroscopy

Recent investigations suggest that thalamic abnormalities may underlie symptom formation in schizophrenia. We previously demonstrated reduced concentrations of N-acetylaspartate (NAA) in tissue from the thalamus of schizophrenic patients using in vitro proton magnetic resonance spectroscopy (1H-MRS). In the present study, in vivo 1H-MR spectra of the left thalamus and frontal lobe were investigated in 20 patients with schizophrenia and 16 age-matched control subjects to replicate our previous postmortem findings and support the hypothesis of thalamic abnormality in schizophrenia. Schizophrenic patients showed significantly lower NAA/total creatine (Cr) and choline-containing compounds (Cho)/Cr ratios in the thalamus than control subjects, while no significant difference was found in the frontal lobe. There was no significant correlation in the schizophrenic patients between the NAA/Cr or Cho/Cr ratio and other clinical data including clinical symptoms or neuroleptic dosage. These findings may further support other studies suggesting decreased thalamic volume or neuronal number and/or thalamic dysfunction, and reduction in size of white matter tracts adjacent to the thalamus in schizophrenia, as well as our previous postmortem MRS study.     

Interneuronal calcium channel abnormalities in posttraumatic epileptogenic neocortex

Decreased release probability (Pr) and increased failure rate for monosynaptic inhibitory postsynaptic currents (IPSCs) indicate abnormalities in presynaptic inhibitory terminals on pyramidal (Pyr) neurons of the undercut (UC) model of posttraumatic epileptogenesis. These indices of inhibition are normalized in high [Ca++] ACSF, suggesting dysfunction of Ca2+ channels in GABAergic terminals. We tested this hypothesis using selective blockers of P/Q and N-type Ca2+ channels whose activation underlies transmitter release in cortical inhibitory terminals. Pharmacologically isolated monosynaptic IPSCs were evoked in layer V Pyr cells by extracellular stimuli in adult rat sensorimotor cortical slices. Local perfusion of 0.2/1 μM ω-agatoxin IVa and/or 1 μM ω-conotoxin GVIA was used to block P/Q and N-type calcium channels, respectively. In control layer V Pyr cells, peak amplitude of eIPSCs was decreased by ~50% after treatment with either 1 μM ω-conotoxin GVIA or 1 μM ω-agatoxin IVa. In contrast, there was a lack of sensitivity to 1 μM ω-conotoxin GVIA in UCs. Immunocytochemical results confirmed decreased perisomatic density of N-channels on Pyr cells in UCs. We suggest that decreased calcium influx via N-type channels in presynaptic GABAergic terminals is a mechanism contributing to decreased inhibitory input onto layer V Pyr cells in this model of cortical posttraumatic epileptogenesis.     

Neuropsychological correlates of P300 abnormalities in patients with schizophrenia and obsessive-compulsive disorder

The cognitive significance of P300 abnormalities in schizophrenia and obsessive-compulsive disorder (OCD) was investigated. P300 was measured by an auditory oddball paradigm, in which a series of standard tones (1000 Hz) and target tones (1500 Hz) were presented. The subject's task was to count the number of the presented target tones. Cognitive functions were evaluated by neuropsychological tests, which were chosen to be sensitive to frontal and temporal dysfunction. Twenty-two schizophrenic patients, 19 OCD patients and 21 healthy controls participated. Event-related potentials measured at 15 electrode sites, which consisted of five levels on the left-right dimension and three levels on the anterior-posterior dimension, were included in the statistical analysis. P300 amplitudes on all 15 electrode sites were significantly smaller in schizophrenic and OCD patients than in the controls. Schizophrenic patients performed poorly on almost all neuropsychological tests, while OCD patients showed impaired performance on the Rey-Osterrieth Complex Figure Test and on a controlled oral word association test. In schizophrenic patients, P300 amplitude was associated with performance on verbal memory and learning by the Luria-Nebraska Neuropsychological Battery, while for OCD patients, P300 amplitude was related to the Trail Making Test, Part B response time. These results indicate that schizophrenic patients have generalized cognitive impairments, which are substrated by a wide range of cortical dysfunctions. The major cognitive deficits observed in OCD patients were impairments of controlled attention and self-guided, flexible behavior, which are mediated by the fronto-striatal system. The neurophysiological mechanisms underlying P300 abnormalities observed in schizophrenic and OCD patients are discussed.     

Anterior cingulum abnormalities in male patients with schizophrenia determined through diffusion tensor imaging

OBJECTIVE: This study used diffusion tensor imaging to examine fractional anisotropy in the anterior cingulum and posterior cingulum bundles in patients with schizophrenia. METHOD: Twenty-one male patients and 20 healthy comparison men were studied. RESULTS: Reduced fractional anisotropy was seen for both sides of the anterior cingulum in the schizophrenia patients, who also exhibited less left-greater-than-right asymmetry in the anterior cingulum than was seen in the comparison subjects. CONCLUSIONS: The findings suggest structural disconnections in the anterior cingulum in patients with schizophrenia.     

Hippocampal‐parietal dysconnectivity and glutamate abnormalities in unmedicated patients with schizophrenia

Abnormalities in resting state connectivity in schizophrenia (SZ) are now well established, but the biological substrates of these functional alterations remain to be elucidated. We performed a combined functional magnetic resonance imaging and magnetic resonance spectroscopy study in 22 unmedicated patients with SZ and 22 matched healthy controls (HCs) to evaluate resting state functional connectivity of the hippocampus and Glx/Cr (a combined glutamate + glutamine peak normalized to creatine) in the hippocampus and investigate functional and neurometabolic abnormalities and examine the relationship between these. Functional connectivity between the left hippocampus and bilateral precuneus was significantly decreased in unmedicated patients with SZ when compared to HCs [t(4.22), cluster extent (kE) = 751, P_FDRcorr = 0.001, Montreal Neurological Institute coordinates: x = ?4, y = ?56, z = 44]. Glx/Cr in the hippocampus was significantly elevated in SZ (HC: mean = 0.60+/?0.10 SZ: 0.67+/?0.10; F = 5.742; P = 0.02), but was not correlated with functional connectivity deficits (P > 0.05). In this study, we found hippocampal resting state functional connectivity deficits to the precuneus in unmedicated patients with SZ and an increase of Glx/Cr in the hippocampus, but did not observe a direct relationship between these abnormalities. However, our findings do not exclude the possibility of a shared underlying pathology, which warrants further investigation. © 2014 Wiley Periodicals, Inc.     

Review of clinical correlates of P50 sensory gating abnormalities in patients with schizophrenia

A large percentage of patients with schizophrenia are characterized by an abnormality in P50 sensory gating. This abnormality has been shown to be genetically linked to the alpha-7 nicotinic receptor and is transiently reversed by acute nicotine administration. These observations have led to the development of pharmacological treatments designed to improve sensory gating. However, if normalization of P50 gating abnormalities is to guide drug development, then it becomes important to delineate the clinical correlates of enhanced P50 gating. We conducted a review of all available articles through March 2005 that have examined this issue. We found that, despite the prominent role that P50 abnormalities have played in our understanding of schizophrenia, there is a relative dearth of data examining P50 clinical correlates. There is evidence suggestive of an association between P50 and measures of attention, and multiple studies have failed to document a cross-sectional or longitudinal relationship between P50 and positive, negative, or other symptoms. These results suggest that considerably more work needs to be done to understand and validate the clinical significance of this impairment.