Avoidant personality disorder symptoms in first-degree relatives of schizophrenia patients predict performance on neurocognitive measures: the UCLA family study.

Whether avoidant personality disorder symptoms are related to neurocognitive impairments that aggregate in relatives of schizophrenics is unknown. We report the relationship between avoidant personality disorder symptoms and neurocognitive performance in the first-degree relatives of probands with schizophrenia. 367 first-degree relatives of probands with schizophrenia and 245 relatives of community controls were interviewed for the presence of avoidant personality symptoms and symptoms of paranoid and schizotypal personality disorders and administered neurocognitive measures. Relationships between neurocognitive measures and avoidant symptoms were analyzed using linear mixed models. Avoidant dimensional scores predicted performance on the span of apprehension (SPAN), 3-7 Continuous Performance Test (3-7 CPT), and Trail Making Test (TMT-B) in schizophrenia relatives. These relationships remained significant on the SPAN even after adjustment for paranoid or schizotypal dimensional scores and on the TMT-B after adjustment for paranoid dimensional scores. Moreover, in a second set of analyses comparing schizophrenia relatives to controls there were significant or trending differences in the degree of the relationship between avoidant symptoms and each of these neurocognitive measures even after adjustments for paranoid and schizotypal dimensional scores. The substantial correlation between avoidant and schizotypal symptoms suggests that these personality disorders are not independent. Avoidant and in some cases schizotypal dimensional scores are significant predictors of variability in these neurocognitive measures. In all analyses, higher levels of avoidant symptoms were associated with worse performance on the neurocognitive measures in relatives of schizophrenia probands. These results support the hypothesis that avoidant personality disorder may be a schizophrenia spectrum phenotype.

Avoidant personality disorder is a separable schizophrenia-spectrum personality disorder even when controlling for the presence of paranoid and schizotypal personality disorders The UCLA family study.

It is unresolved whether avoidant personality disorder (APD) is an independent schizophrenia (Sz)-spectrum personality disorder (PD). Some studies find APD and social anxiety symptoms (Sxs) to be separable dimensions of psychopathology in relatives (Rels) of schizophrenics while other studies find avoidant Sxs to be correlated with schizotypal and paranoid Sxs. Rates of APD among first-degree Rels of Sz probands, attention-deficit/hyperactivity disorder (ADHD) probands, and community control (CC) probands were examined. Further analyses examined rates when controlling for the presence of schizotypal (SPD) and paranoid (PPD) personality disorders, differences in APD Sxs between relative groups, and whether APD in Rels of Szs reflects a near miss for another Sz-spectrum PD. Three hundred sixty-two first-degree Rels of Sz probands, 201 relatives of ADHD probands, and 245 Rels of CC probands were interviewed for the presence of DSM-III-R Axis I and II disorders. Diagnoses, integrating family history, interview information, and medical records, were determined. APD occurred more frequently in Rels of Sz probands compared to CC probands (p<0.001) and also when controlling for SPD and PPD (p<0.005). Two Sxs of APD were most characteristic of the Rels of Sz probands: "avoids social or occupational activities..." and "exaggerates the potential difficulties..." 65% of the Rels of Sz probands who had diagnoses of APD were more than one criterion short of a DSM-III-R diagnosis of either SPD or PPD. This indicates that APD is a separate Sz-spectrum disorder, and not merely a sub-clinical form of SPD or PPD.

Surgery for symptomatic infant-onset epileptic encephalopathy with and without infantile spasms.

Children undergoing surgery with infant-onset epilepsy were classified into those with medically refractory infantile spasms (IS), successfully treated IS, and no IS history, and the groups were compared for pre- and postsurgery clinical and Vineland Adaptive Behavior Scale (VABS) developmental quotients (DQ). Children without an IS history were older at surgery and had longer epilepsy durations than those with IS despite similar substrates, surgeries, and seizure frequencies. In all groups, better postsurgery VABS-DQ scores were associated with early surgical intervention indicating that infant-onset epilepsy patients with or without IS are at risk for seizure-induced encephalopathy.

Cerebral hemispherectomy: hospital course, seizure, developmental, language, and motor outcomes.

OBJECTIVE: To compare hemispherectomy patients with different pathologic substrates for hospital course, seizure, developmental, language, and motor outcomes. METHODS: The authors compared hemispherectomy patients (n = 115) with hemimegalencephaly (HME; n = 16), hemispheric cortical dysplasia (hemi CD; n = 39), Rasmussen encephalitis (RE; n = 21), infarct/ischemia (n = 27), and other/miscellaneous (n = 12) for differences in operative management, postsurgery seizure control, and antiepilepsy drug (AED) usage. In addition, Vineland Adaptive Behavior Scale (VABS) developmental quotients (DQ), language, and motor assessments were performed pre- or postsurgery, or both. RESULTS: Surgically, HME patients had the greatest perioperative blood loss, and the longest surgery time. Fewer HME patients were seizure free or not taking AEDs 1 to 5 years postsurgery, but the differences between pathologic groups were not significant. Postsurgery, 66% of HME patients had little or no language and worse motor scores in the paretic limbs. By contrast, 40 to 50% of hemi CD children showed near normal language and motor assessments, similar to RE and infarct/ischemia cases. VABS DQ scores showed +5 points or more improvement postsurgery in 57% of patients, and hemi CD (+12.7) and HME (+9.1) children showed the most progress compared with RE (+4.6) and infarct/ischemia (-0.6) cases. Postsurgery VABS DQ scores correlated with seizure duration, seizure control, and presurgery DQ scores. CONCLUSIONS: The pathologic substrate predicted pre- and postsurgery differences in outcomes, with hemimegalencephaly (but not hemispheric cortical dysplasia) patients doing worse in several domains. Furthermore, shorter seizure durations, seizure control, and greater presurgery developmental quotients predicted better postsurgery developmental quotients in all patients, irrespective of pathology.

Medial temporal lobe in childhood-onset schizophrenia.

The majority of anatomic and neuroimaging studies in adult-onset schizophrenia demonstrate decreased volumes of the medial temporal lobe when compared with findings in normal individuals. The goal of this study was to investigate the hypothesis that subjects with childhood-onset schizophrenia would show decreased volumes of the medial temporal lobe when compared to normal children. Thirteen children meeting DSM-III-R criteria for schizophrenia (mean age 14.2+/-3.8 years) and 20 normal children (mean age 12.0+/-2.8 years) were investigated. MRI scans were performed on a 1.5-T GE Signa MR scanner using a coronal plane SPGR at 1.4-mm slice thickness. Volumes were assessed by manually tracing bilateral hippocampus, amygdala and temporal lobes. After adjustment for age and total brain volume, the amygdala was significantly larger in the schizophrenics than in the control subjects, and this volume increase was more pronounced on the left side. Hippocampus volumes did not differ significantly across groups. There was a nearly significant left-greater-than-right asymmetry of the amygdala in the schizophrenic group but not in the normal group. A nearly significant right-greater-than-left asymmetry was found in the anterior hippocampus for both schizophrenic and control groups. These findings are consistent with previous reports of at least initial sparing of temporal lobe regions in childhood-onset schizophrenia.

Thought disorder in attention-deficit hyperactivity disorder.

OBJECTIVE: This study compared thought disorder and associated cognitive variables in attention-deficit hyperactivity disorder (ADHD) and schizophrenia. METHOD: Speech samples of 115 ADHD, 88 schizophrenic, and 190 normal children, aged 8 to 15 years, were coded for thought disorder. A structured psychiatric interview, the WISC-R, the Continuous Performance Test, and the Span of Apprehension task were administered to each child. RESULTS: The ADHD and schizophrenic groups had thought disorder compared with the normal children. However, the subjects with ADHD had a narrower range of less severe thought disorder than did the schizophrenic subjects. The younger children with ADHD and schizophrenia had significantly more thought disorder than did the older children with these diagnoses. IQ, attention, and working memory were associated with thought disorder in the ADHD but not the schizophrenic group. CONCLUSIONS: Thought disorder in childhood is not specific to schizophrenia and reflects impaired development of children's communication skills.

Schizophrenia and schizophrenia-spectrum personality disorders in the first-degree relatives of children with schizophrenia: the UCLA family study.

BACKGROUND: This study tested the hypothesis that childhood-onset schizophrenia (COS) is a variant of adult-onset schizophrenia (AOS) by determining if first-degree relatives of COS probands have an increased risk for schizophrenia and schizotypal and paranoid personality disorders. METHODS: Relatives of COS probands (n = 148) were compared with relatives of attention-deficit/hyperactivity disorder (ADHD) (n = 368) and community control (n = 206) probands. Age-appropriate structured diagnostic interviews were used to assign DSM-III-R diagnoses to probands and their relatives. Family psychiatric history was elicited from multiple informants. Diagnoses of relatives were made blind to information about probands' diagnoses. Final consensus diagnoses, which integrated family history, direct interview information, and medical records, are reported in this article. RESULTS: There was an increased lifetime morbid risk for schizophrenia (4.95% +/- 2.16%) and schizotypal personality disorder (4.20% +/- 2.06%) in the parents of COS probands compared with parents of ADHD (0.45% +/- 0.45%, 0.91% +/- 0.63%) and community control (0%) probands. The parents of COS probands diagnosed as having schizophrenia had an early age of first onset of schizophrenia. Risk for avoidant personality disorder (9.41% +/- 3.17%) was increased in the parents of COS probands compared with parents of community controls (1.67% +/- 1.17%). CONCLUSIONS: The psychiatric disorders that do and do not aggregate in the parents of COS probands are remarkably similar to the disorders that do and do not aggregate in the parents of adults with schizophrenia in modern family studies. These findings provide compelling support for the hypothesis of etiological continuity between COS and AOS.

Brain abnormalities observed in childhood-onset schizophrenia: a review of the structural magnetic resonance imaging literature.

Childhood-onset schizophrenia (COS) is a rare, severe form of schizophrenia in which there are structural brain abnormalities that may be related to the psychotic symptomatology and neurocognitive deficits found in these patients. While there are numerous structural imaging studies of the adult-onset variant of schizophrenia (with many conflicting findings), relatively few brain imaging studies of COS have been conducted. This paper summarizes the extant literature of magnetic resonance imaging (MRI) studies of structural brain abnormalities in COS, and compares findings to similar studies of adult-onset patients. Volumetric MRI studies of COS patients have consistently shown evidence for increased ventricular volume, reduced cerebral gray matter, and increased caudate volume, consistent with findings from adult-onset studies. Other volumetric brain abnormalities are observed in COS patients, such as reduced total brain volume, but not consistently across all studies. Voxel-based morphometric analyses have revealed abnormalities in the shape and spatial location of structures in COS such as the corpus callosum, caudate, and thalamus that could not be observed in the more traditional volumetric assessments. Similar findings also are observed in adult-onset patients. Progressive degenerative changes, such as ventricular enlargement, appear to occur in COS only until young adulthood where there is an apparent asymptote with no further degenerative changes. This is consistent with the lack of progressive changes noted in most longitudinal studies of adult-onset schizophrenia.

Brain abnormalities in early-onset schizophrenia spectrum disorder observed with statistical parametric mapping of structural magnetic resonance images.

OBJECTIVE: The purpose of this study was to assess neuroanatomic abnormalities in children and adolescents with childhood-onset schizophrenia by using whole-brain voxel-based morphometric analyses. Previous volumetric studies of brain abnormalities in childhood-onset schizophrenia have revealed anomalies similar to those in subjects with adult-onset schizophrenia. Specifically, low cerebral volume, high ventricular volume, and thalamic, basal ganglia, callosal, and temporal lobe abnormalities have been observed in childhood-onset schizophrenia. Relatively few anatomical structures have been delineated and measured in this rare population, partly because of the labor involved in the slice-by-slice region definition required of conventional volumetric image analyses. METHOD: The subjects were 10 normal children and adolescents and nine children and adolescents with early-onset schizophrenia (mean age at diagnosis, 11.0 years; range, 7-16 years). The authors conducted voxel-by-voxel and volumetric statistical analyses of high-resolution structural magnetic resonance images. RESULTS: Statistical parametric maps of gray matter, white matter, and CSF differences between the groups revealed that the subjects with early-onset schizophrenia had larger ventricles, predominantly in the posterior horns of the lateral ventricles, and midcallosal, posterior cingulate, caudate, and thalamic abnormalities. Volumetric analyses of the lateral ventricles in native image data space confirmed significantly higher volume in posterior, but not anterior, regions. Randomization tests confirmed the overall statistical significance of the group differences and validity of the parametric maps. CONCLUSIONS: These findings are generally consistent with the findings of other research groups, but localization of enlarged ventricles specific to the posterior region may be a new finding in the literature on childhood-onset schizophrenia.

Attention in HIV-infected children: results from the Hemophilia Growth and Development Study.

Attentional functioning was examined in three groups of 7- to 19-year-old male participants with hemophilia: (1) HIV seronegative controls (HIV-, N = 66), (2) HIV seropositive participants with CD4+ lymphocyte counts greater than or equal to 200 (HIV+ CD4+ > or = 200, N = 79), and (3) severely immune suppressed HIV seropositive participants (HIV+ CD4+ < 200, N = 28). Two measures sensitive to attention deficits were used: the Continuous Performance Test (CPT) and the Span of Apprehension (Span). On the CPT, there was a decrement in attention in both HIV+ groups, as indexed by an increase in false alarm rate from Block 1 to Block 3, that was not present in the HIV- group. The longer the HIV+ children were required to sustain attention to the CPT, the more they responded to the incorrect stimulus. This effect decreased as age increased. Span percent correct and latency to correct were associated with the presence of a premorbid history of intracerebral hemorrhage, but were not sensitive to HIV status or degree of immune suppression in the HIV+ children, suggesting morbidity related to hemophilia. The remaining CPT and Span variables--hit rate, sensitivity, latency, percent correct, and latency to correct--showed the expected associations with age, but none showed conclusive associations with HIV status or immune suppression in the HIV+ participants.

Assessment in multisite randomized clinical trials of patients with autistic disorder: the Autism RUPP Network. Research Units on Pediatric Psychopharmacology.

Assessment of autistic disorder (autism) symptoms, primary and secondary, poses more challenging problems than ordinarily found in multisite randomized clinical trial (RCT) assessments. For example, subjects may be uncommunicative and extremely heterogeneous in problem presentation, and current pharmacological treatments are not likely to alter most core features of autism. The Autism Research Units on Pediatric Psychopharmacology (RUPP Autism Network) resolved some of these problems during the design of a risperidone RCT in children/adolescents. The inappropriateness of the usual anchors for a Clinical Global Impression of Severity (CGI-S) was resolved by defining uncomplicated autism without secondary symptoms as a CGI-S of 3, mildly ill. The communication problems, compromising use of the patient as an informant, were addressed by several strategies, including careful questioning of care providers, rating scales, laboratory tests, and physical exams. The broad subject heterogeneity requires outcome measures sensitive to individual change over a wide spectrum of treatment response and side effects. The problems of neuropsychologically testing nonverbal, lower functioning, sometimes noncompliant subjects requires careful instrument selection/adaptation and flexible administration techniques. The problems of assessing low-end IQs, neglected by most standardized test developers, was resolved by an algorithm of test hierarchy. Scarcity of other autism-adapted cognitive and neuropsychological tests and lack of standardization required development of a new, specially adapted battery. Reliability on the Autism Diagnostic Interview (currently the most valid diagnostic instrument) and other clinician instruments required extensive cross-site training (in-person, videotape, and teleconference sessions). Definition of a treatment responder required focus on individually relevant target symptoms, synthesis of possible modest improvements in many domains, and acceptance of attainable though imperfect goals. The assessment strategy developed is implemented in a RCT of risperidone (McDougle et al., 2000) for which the design and other methodological challenges are described elsewhere (Scahill et al., 2000). Some of these problems and solutions are partially shared with RCTs of other treatments and other disorders.

Thought disorder in childhood schizophrenia: replication and update of concept.

OBJECTIVES: To examine whether measures of thought disorder differentiated schizophrenic from normal children and to examine the relationship of these measures with developmental and cognitive factors. METHOD: The speech samples of 88 schizophrenic and 190 normal children, aged 9 to 13 years, were coded with the Kiddie Formal Thought Disorder Rating Scale and Halliday and Hassan's analysis of cohesion. RESULTS: Above and beyond differences in mental age, gender, and neuroleptic status, the patients had significantly more formal thought disorder (FTD) and cohesive deficits than the normal children matched by mental age. The younger schizophrenic and normal children had significantly more thought disorder than the older children with these diagnoses. Combined FTD and cohesion scores correctly identified 76% of schizophrenic and 88% of normal children with little variability across mental age. The thought disorder measures generated 2 independent components: FTD and cohesion. CONCLUSIONS: Thought disorder measures that include both FTD and cohesion provide a quantitative diagnostic tool of childhood-onset schizophrenia.

Accelerated age-related decline in processing resources in schizophrenia: evidence from pupillary responses recorded during the span of apprehension task.

Cognitive impairment in schizophrenia may be related to reduced availability of information-processing resources (resource limitations hypothesis). An abnormally accelerated age-related decline in processing resource availability may also occur in older patients with schizophrenia (neurodegeneration hypothesis). To test these hypotheses, pupillary responses were recorded as an index of processing resource availability during performance of the span of apprehension (SOA) task in 33 middle-aged and older patients with schizophrenia and 37 age-comparable nonpsychiatric participants. Consistent with the resource-limitations hypothesis, the patients with schizophrenia showed impaired detection accuracy and abnormally small pupillary responses (reduced resource allocation) only in the higher processing load SOA conditions. This pattern of results suggests that the patients depleted their available processing resources at lower processing loads than the nonpsychiatric participants. Consistent with the neurodegeneration hypothesis, cross-sectional analyses showed abnormally accelerated rates of age-related decline in SOA performance and pupillary responses in the patients with schizophrenia relative to age-comparable normal participants.

Neuropsychological deficits in pediatric patients with childhood-onset schizophrenia and psychotic disorder not otherwise specified.

OBJECTIVE: Children with transient psychotic symptoms and serious emotional disturbances who do not meet current criteria for schizophrenia or other presently recognized diagnostic categories commonly present diagnostic and treatment problems. Clarifying the connections between children with narrowly defined schizophrenia and children with a more broadly defined phenotype (i.e., Psychotic Disorder Not Otherwise Specified, PD-NOS) has implications for understanding the pathophysiology of schizophrenia. In this study, the neuropsychological test performance of a subgroup of children with atypical psychosis was compared with that of patients with childhood-onset schizophrenia (COS). METHOD: Cognitive function was assessed with neuropsychological test battery regimens in 51 neuroleptic-nonresponsive patients within the first 270 at NIMH testing (24 PD-NOS, 27 COS) were included in this analysis. Seventeen (39%) of 44 COS subjects were unavailable for this study as their IQ tested <70. The PD-NOS patients were younger than the COS patients at the time of testing (12.0+/-2.8 vs 14.4+/-1.8years, respectively, p<0.004). The test levels of these groups were compared with each other. RESULTS: The neuropsychological test results for the PD-NOS and COS patients were 1-2standard deviations below normative data across a broad array of cognitive functions. There were no overall differences in the test levels for the six summary scales (F=2.82, df=1, 36, p=0.10) or in the profile shape (F=1.70, df=5, 180, p=0.14) between the PD-NOS and COS groups. For the COS patients, there was a significant difference between their mean full-scale WISC IQ (84.7+/-16.2) and their average standard scores for both the spelling (97.7+/-16.1, n=23, t=4.0, p=0.001) and reading decoding subtests (97.7+/-13.7, n=23, t=3.7, p=0.001) of the Kaufman Test of Educational Achievement. CONCLUSIONS: Treatment-refractory PD-NOS and COS patients share a similar pattern of generalized cognitive deficits, including deficits in attention, learning and abstraction which are commonly observed in adult patients with schizophrenia. These data support a hypothesis that at least some of the PD-NOS cases belong within the schizophrenic spectrum, which is of importance for future genetic studies planned for this cohort.

Relevance of the cerebellar hemispheres for executive functions.

The aim of the present study was to elucidate the role of the cerebellar hemispheres in executive functions. The findings are relevant because of the large number of children who survive cerebellar tumors. Neuropsychologic assessments of four patients (8-21 years of age) who had undergone neurosurgery for removal of tumors in the cerebellar hemispheres were conducted and compared with the assessments of six children who had been diagnosed with temporal lobe tumors or cysts. The executive functions were assessed using the Wisconsin Card Sorting Test. IQs were average in both groups. As expected, patients with cerebellar hemispheric lesions had impaired executive functions. In particular, they appeared to have difficulty generating and testing hypotheses regarding the matching rules on the Wisconsin Card Sorting Test. Patients with temporal lesions had a different pattern of deficits on this test. The findings are consistent with the theories that propose that the cerebellar hemispheres are involved in cognitive processes. The findings also demonstrate that subtle deficits in executive functions can be masked by a normal IQ in survivors of cerebellar tumors and highlight the need to design interventions targeted toward problem-solving skills.

Normal development of bilateral field advantage and evoked potential interhemispheric transmission time.

Implications of the developmental progression of myelination of the corpus callosum were studied using evoked potential interhemispheric transmission time (EP-IHTT) and the bilateral field advantage (BFA) in letter matching. Forty-two normal children aged 7 to 17 years were asked to respond regarding whether 2 letters matched when presented either unilaterally (both in the same visual field) or bilaterally (1 letter in each field). Evoked potentials were recorded with bilateral midparietal electrodes during unilateral presentations of the letter-matching task. Age-related changes were found for both EP-IHTT and BFA. BFA in reaction time in the visual letter-matching task increased significantly with age. Decreasing EP-IHTT with age was also evident (although only in a statistical trend). These findings lend support to the hypothesis that increased callosal myelination during late childhood has functional significance. Callosal maturation appears to result in faster interhemispheric transfer and increasing ability to integrate information across the midline.

Neurocognitive impairments in schizophrenia: a piece of the epigenetic puzzle.

This paper is a review of studies examining the neurobehavioral antecedents of schizophrenia which flesh out neurodevelopmental models of schizophrenia by detailing the time course of the ontogeney of neurobehavioral impairments in schizophrenia. A follow back design was used to identify precursors of psychotic symptoms in children with a schizophrenic disorder. The vast majority of children with a schizophrenic disorder had significant developmental delays beginning early in life. For example, gross deficits in early language development were found in almost 80% of the schizophrenic children. Somewhat later in development impairments in fine motor and bi-manual coordination are noted. Some of these early developmental delays are transitory. For example, basic language skills are among the best preserved neurocognitive functions in children and adults with schizophrenia. The results of our cross-sectional neurocognitive studies suggest that children with schizophrenia suffer from limitations in the ability to engage in effortful cognitive processing or impairments in working memory. The links between these elementary neurocognitive impairments and the development of formal thought disorder as well as discourse deficits in children with a schizophrenic disorder will be discussed.

Persistent Post-Concussive Syndrome: A proposed methodology and literature review to determine the effects, if any, of mild head and other bodily injury.

Following mild head injury, a subgroup of individuals exhibit a constellation of chronic symptoms, a condition Alexander (1995) labeled Persistent Post-Concussive Syndrome (PPCS). He implicated neurological factors in the initial phase of the syndrome but psychological factors in the maintenance of symptoms. However, it is unclear as to whether an initial mild head injury is necessary or sufficient to cause the symptoms of PPCS. We first outline a study design comparing a mild closed-head injury group to both a normal and an other injury control group to answer this question. Next, we review the literature since 1960 to determine the findings of any studies using this design. The results of the literature review indicate that few such studies exist. To date, those that have been done suggest that there is no strong evidence for a specific effect for mild head injury on cognitive functioning. We discuss directions for future research given these findings.