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Objective: Converging evidence implicates prefrontal circuits in the pathophysiology of bipolar disorder. Proton spectroscopy studies performed in adult bipolar patients assessing prefrontal regions have suggested decreased levels of N-acetylaspartate (NAA), a putative marker of neuronal integrity. In order to examine whether such abnormalities would also be found in younger patients, a [sup.1]H spectroscopy study was conducted that focused on the dorsolateral prefrontal cortex of children and adolescents with bipolar disorder. Method: The authors examined the levels of NAA, creatine plus phosphocreatine, and choline-containing molecules in the left dorsolateral prefrontal cortex of 14 bipolar disorder patients (mean age= 1.5.5 years, SD=3, eight female) and 18 healthy comparison subjects (mean age= 17.3, SD=3.7, seven female) using short echo time, single-voxel in vivo [sup.1]H spectroscopy. Absolute metabolite levels were determined using the water signal as an internal reference. Results: Bipolar patients presented significantly lower NAA levels and a significant inverse correlation between choline-containing molecules and number of previous affective episodes. No differences were found for other metabolites. Conclusions: These findings suggest that young bipolar patients have decreased NAA levels in the dorsolateral prefrontal cortex, similar to what was previously reported in adult patients. Such changes may reflect an underdevelopment of dendritic arborizations and synaptic connections. These neuronal abnormalities in the dorsolateral prefrontal cortex of bipolar disorder youth are unlikely to represent long-term degenerative processes, at least in the subgroup of patients where the illness had relatively early onset.

Objective: In vivo imaging studies have suggested anatomical and functional abnormalities in the anterior cingulate in adults with mood disorders. This anatomical magnetic resonance imaging study examined the cingulate cortex in children and adolescents with bipolar disorder and matched healthy comparison subjects. Method: Sixteen patients (mean age = 15.5 years, SD=3.4) with DSM-IV bipolar disorder and 21 matched healthy comparison subjects (mean age=16.9 years, SD=3.8) were studied. Three-dimensional gradient echo imaging was performed (TR=25 msec, TE=5 msec, slice thickness=1.5 mm) in a 1 .S-T GE Signa magnet. Cingulate volumes were compared by using analysis of covariance, with age and intracranial volume as covariates. Results: The patients with bipolar disorder had significantly smaller mean volumes relative to the healthy subjects in the left anterior cingulate (mean=2.49 [cm.sup.3] [SD=0.28] versus 3.60 [cm.sup.3] [SD-0.12], respectively), left posterior cingulate (2.53 [cm.sup.3] [SD=0.32] versus 2.89 [cm.sup.3] [SD= 0.09]), and right posterior cingulate (2.19 [cm.sup.3] [SD=0.13] versus 2.28 [cm.sup.3] [SD= 0.08]). No significant between-group difference was found for the right anterior cingulate (2.64 [cm.sup.3] [SD=0.21] versus 2.71 [cm.sup.3] [SD-0.10]). Conclusions: The findings indicate smaller cingulate volumes in children and adolescents with bipolar disorder, suggesting that such abnormalities may be present early in the illness course.

Objective: The authors compared the patterns and specificity of premorbid personality dimensions in first-episode schizophrenia patients with those in patients with first-episode nonschizophrenia psychoses and healthy comparison subjects. Method: A series of 63 patients with first-episode schizophrenia and related psychotic disorders, 34 patients with first-episode nonschizophrenia psychoses, and 77 healthy comparison subjects were assessed with the Personality Disorder Evaluation, a semistructured interview schedule that measures personality dimensions. Results: Cluster A as well as cluster C dimensional scores--in particular, the avoidant personality score--were higher for the schizophrenia patients, and cluster B dimensional scores were higher for the patients with nonschizophrenia psychoses. Cluster C dimensional scores, particularly the avoidant personality score, were highly intercorrelated with all cluster A dimensional scores. Conclusions: The observed association between avoidant personality and schizophrenia supports the recent literature on the comorbidity of nonspectrum personality disorders in schizophrenia. This association may be related to shared neurodevelopmentally mediated impairments in social cognition in schizophrenia and some cluster C personality dimensions.

Objective: Neuropathological findings regarding the entorhinal cortex in schizophrenia are conflicting. The authors used structural magnetic resonance imaging to examine the entorhinal cortex volumes of healthy subjects and medication-naive patients experiencing their first episode of psychotic illness. Method: The study included 33 patients with schizophrenia and related disorders, 11 patients with nonschizophrenic disorders, and 43 matched healthy subjects. All subjects were rated on the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms, and volumetric measurements of the entorhinal cortex were obtained for all subjects. The authors examined differences across the groups as well as clinical correlations of entorhinal cortex volumes adjusted for intracranial volume. Results: A significant diagnosis effect was seen in the left entorhinal cortex: patients with schizophrenia and related disorders and patients with nonschizophrenic psychotic disorders had smaller left entorhihal cortex volumes than healthy subjects. The mean entorhinal cortex volume of patients with schizophrenic disorders did not differ from that of patients with nonschizophrenic psychotic disorders. In patients with schizophrenic disorders, the entorhinal cortex volume positively correlated with severity of delusions. The mean entorhinal cortex volume of patients with nondelusional psychotic disorders was significantly smaller than that of patients with delusional psychotic disorders and healthy subjects. Conclusions: Smaller entorhinal cortex volume in first-episode, neurolepticnaive psychotic disorders may not be a confound of the effects of illness chronicity or antipsychotic treatment. Entorhinal cortex pathology appears to have a significant association with positive symptoms, specifically delusions. The impairment of functions in which the entorhinal cortex participates--such as novelty detection, associative learning, and processing episodic, recognition, and autobiographical memory--could be responsible for its association with psychotic disorders and delusions.

Objective: The superior temporal gyrus, a heteromodal auditory and language association cortex, has been found to be smaller in patients with schizophrenia than in normal subjects. However, genetic and/or neurodevelopmental underpinnings of superior temporal gyrus alterations are unknown. Nonpsychotic children with greater genetic risk for schizophrenia exhibit language deficits. The authors studied the superior temporal gyrus in nonpsychotic children at risk for schizophrenia. Method: Magnetic resonance imaging was used to measure the right and left superior temporal gyrus of 29 young nonpsychotic subjects who had a parent with schizophrenia and 27 age- and sex-matched comparison subjects who had no family psychiatric history. Results: After controlling for age and intracranial volume, the authors found that the volumes of the right and left superior temporal gyrus of the subjects at risk for schizophrenia were significantly smaller than those of the comparison subjects. Comparison subjects, but not at-risk subjects, showed an inverse correlation between age and left superior temporal gyrus volume. Conclusions: These findings provide new evidence that superior temporal gyrus abnormalities may result from genetically mediated developmental deviance reflecting greater susceptibility to schizophrenia. Further studies and follow-up will lead to greater understanding of the role of the superior temporal gyrus in the premorbid vulnerability to schizophrenia.

Objective: The profile of neuropsychological impairment associated with unipolar psychotic depression remains unclear. The authors used a neuropsychological test battery to characterize the neuropsychiatric profile of patients with unipolar psychotic depression, relative to that of patients with nonpsychotic unipolar depression, patients with schizophrenia, and healthy comparison subjects. Method: Study subjects included antipsychotic-naive patients with a first episode of psychotic unipolar depression (N=20), antipsychotic-naive and unmedicated patients with nonpsychotic unipolar depression (N=14), antipsychotic-naive patients with first-episode schizophrenia (N=86), and healthy volunteers (N=81). Groups were matched on age, sex, race, education, parental socioeconomic status, and estimated premorbid intelligence. Psychotic patients were followed clinically for 2 years to confirm diagnosis. ALL participants completed a standard neuropsychological battery, including tests of general intelligence, executive function, attention, verbal memory, motor skills, and visual-spatial perception. Results: Patients with psychotic depression had a pattern of neuropsychological dysfunction that was similar to but less severe than that of patients with schizophrenia. In contrast, patients with nonpsychotic unipolar depression had a neuropsychological profile that was similar to that of healthy individuals but that included mild dysfunction on tests of attention. Neuropsychological test performance was generally independent of acute clinical symptoms, but some pairwise group differences were attenuated by covariation for symptom severity. Conclusions: The similar neuropsychological profiles for schizophrenia and psychotic depression suggest that these psychotic disorders may have common pathophysiological features. The dramatic differences in performance between the patients with psychotic depression and those with nonpsychotic depression point to a marked distinction in neurocognitive function associated with the expression of psychosis in depressed patients.

Objective: Neurological abnormalities are frequently seen in patients with first-episode psychotic disorders but are generally considered to be diagnostically nonspecific, neurologically nonlocalizing, and, hence, 'soft.' This study examined the neuroanatomical correlates and diagnostic specificity of abnormal findings on the neurological examination in first-episode schizophrenia and other psychotic disorders. Method: Neuroleptic-naive patients with schizophrenia (N=90) and with nonschizophrenia psychoses (N=39) and carefully matched healthy subjects (N=93) were compared on total and factor scores for a reliable subset of Neurological Evaluation Scale items. The relationship between neurological examination abnormalities and alterations in the relevant brain structures as assessed by magnetic resonance imaging was examined in a subset of subjects. Results: Factor scores for repetitive motor task abnormalities were higher in both patient groups, relative to the healthy group, and did not distinguish between the patient groups. Factor scores for abnormalities in cognitively demanding and perceptual tasks were markedly higher in the schizophrenia group, relative to both comparison groups, and were not different between the nonschizophrenia psychoses group and the healthy comparison group. Higher scores for the cognitive/perceptual abnormalities factor were correlated with smaller volumes of the left heteromodal association cortex. Conclusions: Neurological signs may serve as expedient bedside measures that are potentially useful in the assessment of idiopathic psychoses, and cognitive/ perceptual neurological signs may have a measure of diagnostic specificity. These findings provide neurobiological validation of abnormal findings on the neurological examination. These abnormalities may reflect discrete neuroanatomical alterations in schizophrenia and may have a localizing value.

Objective: Alcohol use disorders (defined as DSM-IV alcohol dependence or abuse) are prevalent and serious problems among adolescents. As adolescence is marked by progressive hippocampal development, this brain region may be particularly susceptible to the adverse effects of adolescent alcohol use disorders. This study compared the hippocampal volumes of adolescents and young adults with adolescent-onset alcohol use disorders to those of healthy matched comparison subjects. Method: Magnetic resonance imaging was used to measure the hippocampal volumes and volumes of comparison brain regions in 12 subjects with alcohol use disorders and 24 comparison subjects matched on age, sex, and handedness. Results: Both left and right hippocampal volumes were significantly smaller in subjects with alcohol use disorders than in comparison subjects. Total hippocampal volume correlated positively with the age at onset and negatively with the duration of the alcohol use disorder. Intracranial, cerebral, and cortical gray and white matter volumes and measures of the mid-sagittal area of the corpus callosum did not differ between groups. Conclusions: In the mature brain, chronic alcohol use disorders are associated with graded global brain dysmorphology. Although the etiology, neuropsychological consequences, and permanence of these hippocampal findings need to be further examined, these findings suggest that, during adolescence, the hippocampus may be particularly susceptible to the adverse effects of alcohol.

Objective: Previous studies, mostly involving neuroleptic-treated patients, have suggested enlarged basal ganglia size in schizophrenia. The authors sought to examine basal ganglia volume in neuroleptic-naive psychotic patients. Method: Magnetic resonance imaging volumetric studies were conducted in newly diagnosed neuroleptic-naive schizophrenic and non-schizophrenic psychotic patients and in matched healthy comparison subjects. Results: Both patient groups had bilaterally reduced caudate, but not putamen, volumes, compared to the healthy subjects, after adjustment for intracranial volume. Conclusions: Decreases in caudate volume in newly diagnosed psychotic patients may be related to the primary pathophysiology of these disorders; prior observations of increased caudate volume may reflect effects of neuroleptic treatment.

Magnetic resonance spectroscopy (MRS) is increasingly being used in research examining brain physiology in psychiatric disorders. MRS is a noninvasive procedure that can measure the levels of isotopes of a number of elements within the brain. These isotopes resonate when an external magnetic field is applied; the frequency varies for each element and a slight variation is observed for the same element within different chemical compounds. By MRS measurement of these frequencies, the amounts of certain chemical compounds in the brain and the changes in the amounts of these compounds can be derived. MRS is often used to measure the levels of phosphorous-containing compounds. Many of these compounds are involved in energy metabolism or are integral components of cell membranes. Research on Alzheimer's disease has shown that the levels of various phospholipids, important components of cell membranes, in Alzheimer's patients are different from levels in subjects without this disease. MRS studies of patients with dementia caused by several areas of tissue destruction have shown alterations in the ratios of phosphorous-containing compounds that are involved in energy metabolism, indicating impairment of energy metabolism in these patients. Isotopes of fluorine can also be measured by MRS. Fluorine compounds are present in only small amounts in the brain, and can therefore be used for tracer studies. In tracer studies, a drug, or other substance such as glucose, is labeled with fluorine before it is given to the patient. MRS can then follow the metabolism of the labeled compound, and may also be used to measure the amount of compounds containing carbon, hydrogen, sodium, and lithium. Psychiatric research using MRS is just beginning, but promises to provide valuable information about brain physiology in psychiatric disorders. (Consumer Summary produced by Reliance Medical Information, Inc.)

Objective: The purpose of this study was to examine cortical thickness in autism in light of the postmortem evidence of cortical abnormalities of the disorder. Method: Magnetic resonance imaging (MRI) scans were acquired from 17 children with autism and 14 healthy compari son subjects, and sulcal and gyral thickness were measured for the total brain and for all lobes. Results: Increases in total cerebral sulcal and gyral thickness were observed in children with autism relative to comparison subjects. Similar findings were noted in the temporal and parietal lobes but not in the frontal and occipital lobes. Conclusions: These preliminary findings indicate that increased cortical thickness may contribute to the increased gray matter volume and total brain size that have been observed in autism and may also be related to anomalies in cortical connectivity.

Objective: This study used 31-phosphorus magnetic resonance spectroscopy ([sup.31]P MRS) to investigate basal ganglia abnormalities in neuroleptic-naive patients with schizophrenia. Method: Nineteen schizophrenia patients and 31 age- and sex-matched healthy comparison subjects underwent [sup.31]P MRS. Results: The phosphocreatine/total phosphorus and phosphocreatine/total ATP ratios in both basal ganglia were significantly lower in patients. Conclusions: Schizophrenia patients showed features of increased metabolism in the basal ganglia consistent with impaired activity of the frontostriatal pathways.

Objective: Anterior cingulate dysfunction has been implicated in the pathophysiology of posttraumatic stress disorder (PTSD). The authors hypothesized that integrity of the anterior cingulate may be affected in childhood PTSD. Method: Single voxel proton magnetic resonance spectroscopy (proton MRS) was used to measure the relative concentration of N-acetylaspartate and creatine, a marker of neural integrity, in the anterior cingulate of 11 children and adolescents who met DSM-IV criteria for PTSD secondary to maltreatment and 11 healthy matched comparison subjects. Results: The ratio of N-acetylaspartate to creatine was significantly lower in the maltreated subjects with PTSD than in the comparison subjects. Conclusions: The lower N-acetylaspartate/creatine ratio in subjects with PTSD suggests that anterior cingulate neuronal metabolism may be altered in childhood PTSD.

Objective: Neuroimaging studies have demonstrated reduced prefrontal cortical blood flow and metabolism in depression, but the neurobehavioral significance of these observations is not yet established. Method: The Wisconsin Card Sorting Test, a widely used neuropsychological index of prefrontal cortical function, was administered to 79 patients with major depression who had been unmedicated for at least 28 days, to 47 patients with schizophrenia who had never received antipsychotic medication, and to 61 healthy comparison subjects. Results: Depressed patients demonstrated significant deficits on multiple Wisconsin Card Sorting Test measures compared with healthy individuals. These deficits were correlated with the severity of depression and were less severe than those demonstrated by patients with schizophrenia. Conclusions: These results provide neuropsychological evidence for significant prefrontal cortical dysfunction in depression.

Sixty-two first-episode psychotic patients who were neuroleptic-naive were studied to examine predictors of acute dystonia after treatment with haloperidol. Twenty-three patients developed dystonia, two of them despite being treated with biperiden. Biperiden significantly prevented dystonic reactions. Dystonia development was significantly related to younger age, severity of illness, and negative symptoms at baseline and showed a trend to be related to positive symptoms as well. No significant effect of gender or diagnosis was found. The authors suggest that young, severely ill patients in their first psychotic episode who have never been treated with neuroleptics might be at higher risk to develop dystonia.

The authors report preliminary findings from an ongoing prospective study of neuroleptic-naive patients with first-break schizophrenia. They evaluated 17 of these patients and 15 normal subjects with a structured neurological examination before the patients received any medical treatment. The patients with schizophrenia showed significantly greater neurological impairment than did the normal comparison subjects.

Objective: The thalamus, a highly evolved sensory and motor gateway to the cortex, has been implicated in the pathophysiology of several illnesses, including schizophrenia. Several studies have suggested thalamic volume differences in patients with schizophrenia, although only a few studies have examined thalamic structure in new-onset patients. Method: The authors used magnetic resonance imaging to measure thalamic volumes in previously untreated patients with first-episode schizophrenia (N=16) relative to those of healthy comparison subjects (N=25). The age range of the patients and comparison subjects was 15 to 45 years of age. Thalamic volumes in the right and left hemispheres were segmented and analyzed, both separately and as total thalamic volume, by a rater blind to clinical data. The thalamus was further segmented into regions that roughly reflected individual thalamic nuclei. Analysis of covariance was used to control for intracranial volume. Results: Right, left, and total thalamic volumes of the patients with schizophrenia were significantly smaller than those of the comparison subjects. Significantly smaller volumes were found in the left central medial subdivision of the patients as well as a smaller volume in the right central medial subdivision that approached significance. These regions primarily comprised the dorsomedial nucleus, a thalamic nucleus thought to be an important component of aberrant circuitry in schizophrenia. Significant volume differences were also seen in the left anterior, right anterior, and right posterior medial subdivisions. Conclusions: These findings suggest significant thalamic volumetric differences between patients with newly diagnosed schizophrenia and healthy comparison subjects. Future analysis of individual thalamic nuclei may reveal important, specific relationships between thalamic abnormalities and schizophrenia. (Am J Psychiatry 2001; 158:618-624)