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Objective: This study investigated the relationship between regional cortical gray matter thinning and symptoms of schizophrenia spectrum personality disorders (PDs) in siblings of patients with childhood-onset schizophrenia (COS)., Method: A total of 66 siblings of patients with COS were assessed for symptoms of schizophrenia spectrum PDs (avoidant, paranoid, schizoid, schizotypal). Structural magnetic resonance images were obtained at approximately 2-year intervals from the siblings and from 62 healthy volunteers matched for age, sex, ethnicity, and handedness. Cortical thickness measures were extracted. Mixed effect regression models were used to test the relationship between symptoms and cortical gray matter thickness in siblings. Cortical thinning was also tested longitudinally in healthy volunteers and siblings., Results: Cortical thinning was found to correlate with symptoms of schizotypal and, to a lesser extent, schizoid PDs. Thinning was most pronounced in the left temporal and parietal lobes and right frontal and parietal regions. Gray matter loss was found to be continuous with that measured in COS. Longitudinal thinning trajectories were found not to differ between siblings and healthy volunteers., Conclusion: The present investigation of cortical thinning in siblings of patients with COS indicates that symptoms of schizophrenia spectrum PDs correlate with regional gray matter loss. This finding supports the idea of cortical thinning as a schizophrenia endophenotype., (Published by Elsevier Inc.)

Objective: Psychosocial trauma during childhood is associated with schizophrenia vulnerability. The pattern of grey matter decrease is similar to brain alterations seen in schizophrenia. Our objective was to explore the links between childhood trauma, brain morphology and schizophrenia symptoms., Method: Twenty-one patients with schizophrenia stabilized with atypical antipsychotic monotherapy and 30 healthy control subjects completed the study. Anatomical MRI images were analysed using optimized voxel-based morphometry (VBM). Childhood trauma was assessed with the Childhood Trauma Questionnaire, and symptoms were rated on the Scale for the Assessment of Negative Symptoms (SANS) and Scale for the Assessment of Positive Symptoms (SAPS) (disorganization, positive and negative symptoms). In the schizophrenia group, we used structural equation modelling in a path analysis., Results: Total grey matter volume was negatively associated with emotional neglect (EN) in patients with schizophrenia. Whole-brain VBM analyses of grey matter in the schizophrenia group revealed a specific inversed association between EN and the right dorsolateral prefrontal cortex (DLPFC). Path analyses identified a well-fitted model in which EN predicted grey matter density in DLPFC, which in turn predicted the disorganization score., Conclusion: Our findings suggest that EN during childhood could have an impact on psychopathology in schizophrenia, which would be mediated by developmental effects on brain regions such as the DLPFC., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This paper reports the results of replicative analysis of associations of 15 SNPs in a region of 14 genes previously identified in genome-wide association studies (GWAS) with early-onset schizophrenia in Kazakhs. An association of early-onset schizophrenia with genetic markers in three genes (VRK2, KCNB2, and CPVL) was found. An association of rs2312147 in the VRK2 gene with schizophrenia was also previously reported in the Chinese population, so this marker may be considered as possibly race-specific. Two groups consisting of four and six genes demonstrating intergenic epistatic interactions were revealed by multifactor dimensionality reduction methods. The gene ontologies of 14 studied genes were reduced to variants of one molecular function (peptidase activity) and one biological process (positive regulation of biosynthesis processes). Bioinformatic analysis of the protein-protein interactions of products of the genes under study demonstrates that the products of six out of 14 genes may be involved in a single interrelated network, the major connecting link of which is represented by their ubiquitination by the UBC protein.

The insular cortex (insula), whose normal function involves delineating the boundary between self and non-self stimuli, has been implicated in the pathophysiology of the positive symptoms of schizophrenia, including hallucinations and delusions. Childhood-onset schizophrenia (COS), that includes the onset of psychosis before age 13, is a severe and continuous form of the illness which shows profound and global progressive cortical brain abnormalities during adolescence which merge in the adult pattern with age. Using prospectively acquired anatomic brain magnetic resonance imaging (MRI) scans, a matched sample of COS patients, their nonpsychotic full siblings and healthy volunteers, we measured insular volume using the FreeSurfer automated software. COS patients (n=98; 234 scans) had significantly lower right (p=0.003), left (p<0.001), and total (p<0.001) insular volumes than healthy volunteers (n=100; 248 scans). Right insular volume negatively correlated with positive symptoms as measured by the Scale for the Assessment of Positive Symptoms (SAPS) (p=0.02), while both left (p=0.01) and right (p=0.006) insula volumes were positively correlated with overall functioning, as measured by the Children's Global Assessment Scale (CGAS) scores. COS siblings (n=71; 153 scans), on the other hand, did not differ significantly from normal volunteers suggesting that the insular deficits are more related to the illness state than a familial endophenotype. These results also highlight the salience of the insula in positive symptoms of schizophrenia perhaps resulting from the inability to discriminate between self from the non-self in COS. Further work to connect insular deficits to other neurocircuitries is warranted., (Published by Elsevier Ltd.)

Objective: The hippocampus has been implicated in the pathogenesis of schizophrenia, and hippocampal volume deficits have been a consistently reported abnormality, but the subregional specificity of the deficits remains unknown. The authors explored the nature and developmental trajectory of subregional shape abnormalities of the hippocampus in patients with childhood-onset schizophrenia (COS), their healthy siblings, and healthy volunteers., Method: Two hundred twenty-five anatomic brain magnetic resonance images were obtained from 103 patients with COS, 169 from their 79 healthy siblings, and 255 from 101 age- and sex-matched healthy volunteers (age range = 9-29 years). The hippocampus was segmented using FreeSurfer automated image analysis software, and hippocampal shape was evaluated by comparing subjects at more than 6,000 vertices on the left and right hippocampal surfaces. Longitudinal data were examined using mixed model regression analysis., Results: Patients with COS showed significant bilateral inward deformation in the anterior hippocampus. Healthy siblings also showed a trend for anterior inward deformation. However, the trajectory of shape change did not differ significantly between the groups. Inward deformations in the anterior hippocampus were positively related to positive symptom severity, whereas outward surface displacement was positively related to overall functioning., Conclusion: This is the first and largest longitudinal three-way analysis of subregional hippocampal shape abnormalities in patients with COS and their healthy siblings compared with healthy controls. The anterior hippocampal abnormalities in COS suggest the pathophysiologic importance of this subregion in schizophrenia. The trend level and overlapping shape abnormalities in the healthy siblings suggest a more subtle, subregionally specific neuroanatomic endophenotype., (Published by Elsevier Inc.)

The corpus callosum (CC) has been implicated in the pathogenesis of schizophrenia, and CC deficits have been reported in adults with schizophrenia. We explored the developmental trajectory of the corpus callosum in childhood-onset schizophrenia (COS) patients, their healthy siblings (SIB) and healthy volunteers. We obtained 235 anatomic brain magnetic resonance imaging (MRI) scans from 98 COS patients, 153 scans from 71 of their healthy siblings, and 253 scans from 100 age- and gender-matched healthy volunteers, across ages 9-30 years. The volumes of five sub-regions of the CC were calculated using FreeSurfer, and summed to give the total volume. Longitudinal data were examined using mixed model regression analysis. There were no significant differences for the total or sub-regional CC volumes between the three groups. There were also no significant differences between the groups for developmental trajectory (slope) of the CC. This is the largest longitudinal study of CC development in schizophrenia and the first COS study of the CC to include healthy siblings. Overall, CC volume and growth trajectory did not differ between COS patients, healthy siblings, or healthy volunteers. These results suggest that CC development, at least at a macroscopic level, may not be a salient feature of schizophrenia., (Published by Elsevier Ireland Ltd.)

Background: Progressive cortical gray matter (GM) abnormalities are an established feature of schizophrenia and are more pronounced in rare, severe, and treatment refractory childhood-onset schizophrenia (COS) cases. The effect of sex on brain development in schizophrenia is poorly understood and studies to date have produced inconsistent results., Methods: Using the largest to date longitudinal sample of COS cases (n = 104, scans = 249, Male/Female [M/F] = 57/47), we compared COS sex differences with sex differences in a sample of matched typically developing children (n = 104, scans = 244, M/F = 57/47), to determine whether or not sex had differential effects on cortical and subcortical brain development in COS., Results: Our results showed no significant differential sex effects in COS for either GM cortical thickness or subcortical volume development (sex × diagnosis × age interaction; false discovery rate q = 0.05)., Conclusion: Sex appears to play a similar role in cortical and subcortical GM development in COS as it does in normally developing children.

Background: Neuroanatomic studies have not yet addressed how subtle phenotypic distinctions in psychosis alter the underlying brain changes, and whether there is evidence for psychosis as a dimensional construct. We explored the relationship of cortical GM thickness to psychotic phenotypes in children., Methods: Cross-sectional comparison of anatomic brain imaging between patients referred as childhood-onset schizophrenia (COS) but ruled out after a drug free inpatient observation. Groups included: patients with no evidence of psychosis (n=22) after drug free observation, patients with psychosis not otherwise specified (PNOS; total n=29) further divided into those without other axis I diagnoses (n=13) and those with other axis I comorbidities (n=16), age/sex matched COS patients (n=48), and 51 matched healthy controls. GM cortical thickness was compared between the groups, and regressed on patients' SAPS, SANS and GAS scores., Results: Patients with no evidence of psychosis showed no cortical GM deficits. Presence of psychosis (PNOS with or without co-morbidities) showed some areas of temporal and prefrontal deficits, more subtle compared to the extensive bilateral cortical deficits seen for COS. GAS SAPS and SANS scores showed a relationship with cortical GM thickness although it did not survive adjustment for multiple comparisons., Conclusions: These results highlight the need for careful phenotypic characterization, as subtle diagnostic distinctions appear to reflect distinct underlying patterns of brain deficits. The incremental nature of cortical deficits from no psychosis to PNOS to COS may further support dimensional model for psychosis., (Published by Elsevier B.V.)

The treatment of refractory schizophrenia has been a clinical challenge for most psychiatrists; the possible reasons include diagnostic errors, medical conditions and brain dysgenesis. Here, we described a patient with childhood-onset schizophrenia who had severe psychiatric symptoms such as auditory hallucinations and persecutory delusions, and etc. We reexamined all his possible medical conditions and found that the patient had an abnormally enlarged cavus septum pellucidum (CSP) combined with cavum vergae (CV) (maximum length >30 mm). Some reports suggested that abnormal CSP (length >6 mm) has a significant association with schizophrenia. However, abnormally large CSP or CSP/CV and related prognosis were reported rarely. This case suggested that abnormally enlarged CSP or CSP/CV may worsen the prognosis.

Objective: Although magnetic resonance spectroscopy has identified metabolic abnormalities in adult and childhood schizophrenia, no prior studies have investigated the relationship between neurometabolites and thought disorder. This study examined this association in language-related brain regions using proton magnetic resonance spectroscopic imaging ((1)H MRSI)., Method: MRSI was acquired bilaterally from 28 youth with childhood-onset schizophrenia and 34 healthy control subjects in inferior frontal, middle frontal, and superior temporal gyri at 1.5T and short echo time (TR/TE = 1500/30 ms). CSF-corrected "total NAA" (tNAA; N-acetyl-aspartate + N-acetyl-aspartyl-glutamate), glutamate + glutamine (Glx), creatine + phosphocreatine (Cr + PCr), choline compounds (Cho), and myo-inositol (mI) were assayed in manually drawn regions-of-interest partitioned into gray matter, white matter, and CSF and then coregistered with MRSI. Speech samples of all subjects were coded for thought disorder., Results: In the schizophrenia group, the severity of formal thought disorder correlated significantly with tNAA in the left inferior frontal and superior temporal gyri and with Cr + PCr in left superior temporal gyrus., Conclusions: Neurometabolite concentrations in language-related brain regions are associated with thought disorder in childhood-onset schizophrenia., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The goal of the study is to determine the extent of structural brain abnormalities in a multicenter sample of children and adolescents with a recent-onset first episode of psychosis (FEP), compared with a sample of healthy controls. Total brain and lobar volumes and those of gray matter (GM), white matter, and cerebrospinal fluid (CSF) were measured in 92 patients with a FEP and in 94 controls, matched for age, gender, and years of education. Male patients (n = 64) showed several significant differences when compared with controls (n = 61). GM volume in male patients was reduced in the whole brain and in frontal and parietal lobes compared with controls. Total CSF volume and frontal, temporal, and right parietal CSF volumes were also increased in male patients. Within patients, those with a further diagnosis of "schizophrenia" or "other psychosis" showed a pattern similar to the group of all patients relative to controls. However, bipolar patients showed fewer differences relative to controls. In female patients, only the schizophrenia group showed differences relative to controls, in frontal CSF. GM deficit in male patients with a first episode correlated with negative symptoms. Our study suggests that at least part of the GM deficit in children and adolescent-onset schizophrenia and in other psychosis occurs before onset of the first positive symptoms and that, contrary to what has been shown in children-onset schizophrenia, frontal GM deficits are probably present from the first appearance of positive symptoms in children and adolescents.

Meta-analyses in adult-onset schizophrenia report loss of normal planum temporale (PT) asymmetry, posited to relate to language and symptoms, but are inconclusive regarding global "cerebral torque". PT asymmetry has been reported unchanged in childhood onset schizophrenia. Here the discrepancy is examined in adolescence. Unbiased PT asymmetry and torque measures were obtained on 35 adolescents with schizophrenia or schizoaffective disorder and 31 adolescent controls. Patients had less PT asymmetry than controls, but torque was unchanged. Taken with previous reports, these results in adolescent onset psychosis suggest that local disturbance of cerebral asymmetry increases with patient age; it could indicate that differential rate of change at the cortical surface in the two hemispheres is the mechanism of symptom generation., ((c) 2010 Elsevier B.V. All rights reserved.)

Background: Little is known about the effects of antipsychotic medications on gray matter (GM) in schizophrenia. Although clozapine remains the most effective antipsychotic medication in treatment-refractory cases, it is unknown whether it has a differential effect on GM development., Methods: In an exploratory analysis, we used automated cortical thickness measurements and prospectively scanned childhood-onset schizophrenia (COS) patients who were maintained on one medication. Two atypical antipsychotic medications, clozapine (n=12, 37 scans) and olanzapine (n=12, 33 scans) were compared with respect to effects on cortical development, in contrast to GM trajectories of matched controls., Results: There were no significant differences in the trajectories of cortical thickness between the two treatment groups with the exception of a small circumscribed area in the right prefrontal cortex, where the olanzapine group showed thicker cortex. As expected, both groups showed thinner GM compared to matched controls., Conclusions: Although these analyses do not rule out effects of antipsychotic medications on GM development in schizophrenia, they show no differential effect between clozapine and olanzapine on GM trajectory.

We report here the case of a hospitalized 11 year-old boy (YP) with a positive diagnosis of 'Childhood Onset Schizophrenia'. YP experienced verbal-auditory hallucinations, a delusion of alien control and hetero-aggressive behaviour. Antipsychotic drugs were unsuccessful and furthermore provoked severe acute dystonia. fMRI-guided rTMS applied over several cortical regions provided the means to reveal for the first time a functional dissociation between auditory-verbal hallucinations and agency. These results demonstrate the efficacy of rTMS for young patients suffering from drug-resistant hallucinations but they furthermore question the physiopathology of the hallucinatory process by suggesting that agency and hallucinations may be sub-served by different neural networks.

Earlier studies revealed progressive cortical gray matter (GM) loss in childhood-onset schizophrenia (COS) across both lateral and medial surfaces of the developing brain. Here, we use tensor-based morphometry to visualize white matter (WM) growth abnormalities in COS throughout the brain. Using high-dimensional elastic image registration, we compared 3D maps of local WM growth rates in COS patients and healthy children over a 5-year period, based on analyzing longitudinal brain MRIs from 12 COS patients and 12 healthy controls matched for age, gender, and scan interval. COS patients showed up to 2.2% slower growth rates per year than healthy controls in WM (P = 0.02, all P values corrected). The greatest differences were in the right hemisphere (P = 0.006). This asymmetry was attributable to a right slower than left hemisphere growth rate mapped in COS patients (P = 0.037) but not in healthy controls. WM growth rates reached 2.6% per year in healthy controls (P = 0.0002). COS patients showed only a 1.3% per year trend for growth in the left hemisphere (P = 0.066). In COS, WM growth rates were associated with improvement in the Children's Global Assessment Scale (R = 0.64, P = 0.029). Growth rates were reduced throughout the brain in COS, but this process appeared to progress in a front-to-back (frontal-parietal) fashion, and this effect was not attributable to lower IQ. Growth rates were correlated with functional prognosis and were visualized as detailed 3D maps. Finally, these findings also confirm that the progressive GM deficits seen in schizophrenia are not the result of WM overgrowth.

The hypothesis that schizophrenia involves aberrant inter-hemispheric communication has a long pedigree, however its precise role remains unclear. We therefore report the case of a total agenesis of the corpus callosum in a 21-year-old man with childhood-onset schizophrenia. The presence of schizophrenia with very early onset on absence of corpus callosum offers an opportunity to examine neurodevelopmental model and theories regarding to interhemispheric communication in the pathogenesis of psychosis.

Objective: Childhood- and adolescence-onset schizophrenic patients with obsessive-compulsive symptoms (OCS) constitute a specific subgroup of schizophrenia. We performed magnetic resonance imaging in this group seeking evidence of neurodevelopmental insults., Method: Thirty-two schizophrenic patients were compared with 19 controls. Schizophrenic subjects were divided into 15 patients with OCS (SOCS+ group; onset at 15.5 +/- 1.6 years) and 17 without OCS (SOCS- group; onset at 15.3 +/- 1.3 years). Areas of the hippocampus, frontal lobe, corpus callosum and putamen were analysed morphometrically., Results: The left hippocampus was significantly smaller in the SOCS+ group than in the SOCS- and control groups., Conclusion: Reduced size of the left hippocampus in the SOCS+ group supports a neurodevelopmental etiology in this subgroup.

Objectives: To review recent neuroimaging studies of serious emotional disorders in youth and identify problems and promise of neuroimaging in clinical practice., Method: Published reports from refereed journals are briefly described, critiqued, and synthesized into a summary of the findings to date., Results: Childhood-onset schizophrenia shows progressive ventricular enlargement, reduction in total brain and thalamus volume, changes in temporal lobe structures, and reductions in frontal metabolism. Autistic disorder is associated with cerebellar changes, greater total brain and lateral ventricle volume, and asymmetry. The prefrontal cortex and the basal ganglia are consistently reported as abnormal in attention-deficit/hyperactivity disorder. Patients with anorexia nervosa show enlarged CSF spaces and reductions in gray and white matter that are only partially reversible with weight recovery., Conclusions: Results from neuroimaging studies of childhood-onset psychiatric disorders suggest consistency in the structures found to be abnormal, but inconsistencies in the nature of these abnormalities. Although neuroimaging technology holds great promise for neurodevelopmental research, it is not yet a diagnostic instrument.

Childhood-onset schizophrenia (with an onset of psychosis by age 12) is a rare and severe form of the disorder which is clinically and neurobiologically continuous with the adult-onset disorder. Very early onset diseases provide an opportunity to look for more salient or striking risk or etiologic factors in a possibly more homogenous patient population. For the 47 patients with very early onset schizophrenia studied to date, there were more severe premorbid neurodevelopmental abnormalities, more cytogenetic anomalies, and potentially greater family histories of schizophrenia and associated spectrum disorders than later onset cases. There was no evidence for relatively increased obstetrical complications or environmental stress. These data, while preliminary, suggest a very early age of onset of schizophrenia may be secondary to greater genetic vulnerability. It is anticipated that future genetic studies of these patients may provide important etiologic information.

Objective: Multislice proton magnetic resonance spectroscopic imaging (1H-MRSI) permits simultaneous acquisition and mapping of signal intensities of N-acetyl-containing compounds (mainly N-acetylaspartate, NAA), choline-containing compounds (CHO), and creatine plus phosphocreatine (CRE) from multiple whole-brain slices consisting of small single-volume elements. Previous 1H-MRSI studies of adult patients with schizophrenia showed small NAA relative signals in the hippocampal area and in the dorsolateral prefrontal cortex in comparison with healthy subjects. As part of a program to address the pathophysiological continuity between childhood-onset and adult-onset schizophrenia, the authors performed 1H-MRSI of patients with childhood-onset schizophrenia to specifically test whether the hippocampal area and dorsolateral prefrontal cortex show the same abnormalities as seen in adult-onset schizophrenia., Method: A 1.5-T nuclear magnetic resonance machine was used to test 14 patients (mean age, 16.4 years) and 14 comparison subjects. Ratios of areas under the metabolite peaks of the proton spectra were determined (i.e., NAA/CRE, NAA/CHO, CHO/CRE) for multiple cortical and subcortical regions., Results: The patients showed significantly lower NAA/CRE ratios bilaterally in the hippocampal area and the dorsolateral prefrontal cortex than the comparison subjects. There were no significant differences in CHO/CRE or in NAA ratios in any other area sampled., Conclusions: The present study shows that patients with childhood-onset schizophrenia have smaller than normal regional NAA relative signals, suggesting neuronal damage or malfunction in the hippocampal area and dorsolateral prefrontal cortex. These differences were similar in magnitude to those found in patients with adult-onset schizophrenia. The present data extend other evidence of a biological continuum between childhood- and adult-onset schizophrenia.

Objective: Patients with schizophrenia have been reported to have a higher frequency of enlarged cavum septi pellucidi (CSP) in comparison with normal subjects. Neurodevelopmental models of schizophrenia suggest that the more severe the brain dysgenesis, the earlier the onset of psychotic symptoms. Study of patients with childhood-onset schizophrenia allows the opportunity to test this hypothesis., Method: Two groups of subjects were evaluated: healthy volunteers (N=95, mean age=11.7 years) and patients with childhood-onset schizophrenia (N=24, mean age=14.6 years). Magnetic resonance images of 1-mm resampled contiguous brain slices were rated blind to diagnosis. The size of the CSP was recorded as the number of consecutive slices in which the CSP was present. Abnormal enlargement was defined as a CSP greater than 6 mm in length., Results: The frequency of an enlarged CSP was significantly higher in the patient group: 12.5% (three of 24 subjects) versus 1.1% (one of 95 subjects). Also, two of the three patients with an enlarged CSP had complete nonfusion of the septal leaflets, a more severe anomaly than was found in the one comparison subject with an enlarged CSP and typically more severe than anomalies seen in groups with adult-onset schizophrenia., Conclusions: These findings suggest that patients with extremely early-onset (childhood) forms of schizophrenia may have more severe developmental brain anomalies than those with adult onset.

Abnormalities of the smooth pursuit eye movements of adults with schizophrenia have been well described. We examined smooth pursuit eye movements in schizophrenic children, contrasting them with normal and attention-deficit hyperactivity disorder (ADHD) subjects, to determine whether there is continuity of eye movement dysfunction between childhood- and adult-onset forms of schizophrenia. Seventeen schizophrenic children with onset of illness by age 12, 18 ADHD children, and 22 normal children were studied while engaged in a smooth pursuit eye tracking task. Eye tracking variables were compared across the three groups. Schizophrenic children exhibited significantly greater smooth pursuit impairments than either normal or ADHD subjects. Within the schizophrenic group, there were no significant relationships between eye tracking variables and clinical variables, or ventricular/brain ratio. Childhood-onset schizophrenia is associated with a similar pattern of smooth pursuit abnormalities to that seen in later-onset schizophrenia.

Objective: Neurodevelopmental models of schizophrenia imply that a more severe early brain lesion may produce earlier onset of psychotic symptoms. The medial temporal lobes have been proposed as possible locations for such a lesion. The authors tested this hypothesis in a group of children and adolescents with childhood-onset schizophrenia who had severe, chronic symptoms and who were refractory to treatment with typical neuroleptics., Method: Anatomic brain magnetic resonance imaging scans were acquired with a 1.5-T scanner for 21 patients (mean age=14.6 years, SD=2.1) who had onset of schizophrenia by age 12 (mean age at onset=10.2, SD=1.5) and 41 normal children. Volumes of the temporal lobe, superior temporal gyrus, amygdala, and hippocampus were measured by manually outlining these structures on contiguous 2-mm thick coronal slices., Results: Patients with childhood-onset schizophrenia had significantly smaller cerebral volumes. With no adjustment for brain volume, no diagnostic differences were observed for any temporal lobe structure. Unexpectedly, with adjustment for total cerebral volume, larger volumes of the superior temporal gyrus and its posterior segment and a trend toward larger temporal lobe volume emerged for the patients with schizophrenia. These patients lacked the normal (right-greater-than-left) hippocampal asymmetry., Conclusions: These findings do not indicate a more severe medial temporal lobe lesion as the basis of very early onset schizophrenia.

The ventral tegmental area (VTA) is the major dopaminergic (DA) center responsible for the innervation of the prefrontal cortex, nucleus accumbens, and entorhinal region. These areas have been causally implicated in schizophrenia. Thus, the existence of brainstem pathology could explain many of the previously reported findings in schizophrenic (SC) patients. The authors focus on uncovering brainstem abnormalities in schizophrenia by studying the autopsied material of a patient having an early onset of symptomatology. The patient was evaluated at the age of 10 years for manneristic behavior, a speech disorder, and violence. Prominent auditory hallucinations became apparent years later. His mental status and ability for self-care steadily deteriorated until he succumbed to pneumonia at age 22. Microscopic examination of the brain showed central chromatolysis of neurons and mild gliosis in a restricted distribution of the brainstem and thalamus. Cell loss and cytoarchitectural disruption were evident in the frontal lobes, prepyriform cortex, and entorhinal region. The neuropathological changes were interpreted as a chronic derangement in the function of neurons of the rostral brainstem tegmental area and medial thalamus with secondary involvement of their terminal projection sites.

On the basis of a search of the literature and extensive inquiries to clinicians, this paper catalogues those cases that contain any information concerning possible neuropathologic changes in cases of childhood autism or psychosis. In all, 33 cases were identified. Twenty-nine cases are from the literature; six of these are sibling pairs. Four cases were folnd by inquiry and have not been reported heretofore. Because of limitations in both the clinical and neuropathologic data in most of the case reports, the paper serves primarily as a source of reference to the 33 cases identified. The information that is available is presented along with some tentative suggestions for further research.

Four hypotonic boys (aged 4 years and 11 months, 6 years and 9 months, 7 years and 4 months, and 8 years and 10 months, respectively), all of whom demonstrated a formal thought disorder, had been psychotic for more than six months, and met the DSM-III criteria for chronic undifferentiated schizophrenia, were studied with respect to skeletal muscle morphology. A significant difference between the mean fiber diameters of type I and type II muscle fibers was observed in the three boys with the most severe thought disorder, type II muscle fibers being consistently smaller. No significant difference in the mean fiber diameter between the two fiber types were seen in the fourth boy, who was also the only one who demonstrated any secondary thought process. The boys differed in their activity levels, but there was no correlation between type II muscle fiber atrophy and hypoactivity. It is hypothesized that a depressed cholinergic system is implicated in the pathogenesis of both the muscle fiber atrophy and the formal thought disorder.

Two hypotonic boys, aged 7 years, 3 months and 7 yers, 7 months, who possessed sufficient speech to demonstrate a severe thought disorder and who differed markedly in their activity levels, were subjected to a biopsy of the quadriceps muscle. The biopsies revealed atrophy of type 2 muscle fibers, as well as variability in the size of these fibers. The findings could be compatible with a denervation phenomenon.