Frontostriatal disorder of cerebral metabolism in never-medicated schizophrenics.

We scanned 18 patients with schizophrenia who had never received neuroleptic medication and 20 age- and sex-matched controls by positron emission tomography with 18-F-fluorodeoxyglucose (fludeoxyglucose F 18) as a tracer of glucose metabolism. Subjects performed the Continuous Performance Test during 18-F-fluorodeoxyglucose uptake. Scan results were converted to metabolic rates, and computer algorithms were used to identify cortical regions. Previous reports of relative hypofrontality in schizophrenia were confirmed, indicating that this finding is not an artifact of previous treatment. Significantly reduced ratios of inferior and medial frontal regions to occipital cortex were found, together with diminished metabolism in the basal ganglia. This suggests the presence of a combined frontostriatal dysfunction in schizophrenia.

Asymmetric rotational (circling) behavior, a dopamine-related asymmetry: preliminary findings in unmedicated and never-medicated schizophrenic patients.

Circling behavior is one of the best understood behaviors in animals. It is, for the most part, dopaminergically mediated and related to asymmetry in dopaminergic activity between the left and right basal ganglia or left and right frontal cortex. As a rule, animals rotate toward the hemisphere with lower striatal dopaminergic activity. A direct technique to find human analogs of circling behavior was not available. We have developed an automated rotometer with which we can apply the circling rodent model to humans. Left-prone circling behavior (neglect of right-sided turning) was found in 10 unmedicated schizophrenic patients, whereas 85 normal controls demonstrated almost equal right and left turning. These preliminary results may suggest the presence of a dopaminergic asymmetry in some unmedicated schizophrenic patients; that is, right anterior subcortical or cortical structures of the brain may manifest a relative dopaminergic overactivity compared to left anterior structures in at least some unmedicated patients with schizophrenia.

Delayed emergence of striatal dopaminergic hyperactivity after anterolateral ischemic cortical lesions in humans; evidence from turning behavior.

To test the hypothesis that striatal dopaminergic hyperactivity in humans may be an aftermath of anterior cortical ischemic insults, we utilized earlier observations that in several species, including humans with hemiparkinson's disease, asymmetric striatal dopaminergic activity results in spontaneous asymmetric turning away from the hemisphere with higher dopaminergic activity. In this study, electronic monitoring showed that, compared to normal controls, outpatients with old frontal and inferior-parietal cortical strokes exhibit a marked tendency to turn away from the side of the lesion. This delayed ipsilateral neglect suggests a delayed emergence of lasting ipsilateral striatal dopaminergic hyperactivity after unilateral anterolateral cortical insult in humans. Old ischemic insults to anterolateral cortical areas could be one etiological mechanism in human brain disorders that are associated with cortical dysfunction and delayed subcortical dopamine hyperactivity.

Lack of evidence for a role of T-cell-associated retroviruses as an etiology of schizophrenia.

The evidence that schizophrenia may involve infection by a virus (or viruses) has been indirect. The recent discovery, however, of the human retroviruses--human T-cell lymphoma-leukemia virus-I, and II (HTLV-I, -II) and human immunodeficiency virus (HIV)--now also known to affect the central nervous system (CNS), together with the development of new techniques in retrovirology, have made it possible to investigate more directly the role of this class of viruses as an etiology of schizophrenia. In our first effort to screen for the presence of a T-cell lymphotropic virus in schizophrenia, short-term tissue cultures of peripheral lymphocytes from 17 chronic schizophrenic patients and 10 normal controls were established. The cells were cultured in the presence of T-cell growth factor (TCGF, IL-2), and the culture supernatants were tested for the presence of the retroviral enzyme reverse transcriptase. No T-cell-associated reverse transcriptase activity was detected in cultures from patients or normal controls. Therefore, the data do not provide evidence for a role for T-cell lymphotropic retroviruses as an etiology of schizophrenia.

Clinical and instrumental assessment of neuroleptic-induced parkinsonism in patients with tardive dyskinesia.

We evaluated 21 right-handed psychiatric patients with tardive dyskinesia (TD) for the presence and laterality of neuroleptic-induced tremor and rigidity. The goals of the study were to assess the frequency and coexistence of TD and neuroleptic-induced parkinsonism (NIP) using instrumental and clinical measurements and to evaluate the hypothesis that when TD and NIP coexisted in the same patient, they were more likely to appear in opposite limbs. Results indicated that a high percentage of TD patients had coexisting rigidity and tremor on the basis of both clinical ratings and instrumental procedures; however, only instrumental procedures were useful in identifying tremor and rigidity asymmetries. We found that TD and tremor or rigidity did not lateralize to opposite limbs, thus weakening the hypothesis that TD and NIP stemmed from reciprocal pathophysiological mechanisms.

Subtle signs of prenatal maldevelopment of the hand ectoderm in schizophrenia: a preliminary monozygotic twin study.

Genes that predispose to psychosis may act by making individuals more vulnerable to the disruptive effects of various prenatal insults. Fetal organogenesis is mostly completed in the first prenatal trimester. The second trimester is a critical period of massive neuronal migration from the periventricular germinal matrix to the cortex. A peripheral appendage developing simultaneously with this neural migration to the cortex is the distal upper limb. The ectodermal cells of the fetal upper limb migrate to form the hand skin during the fourth and fifth months of gestation (first two-thirds of the second prenatal trimester). Discrepancies in hand morphology between two identical (monozygotic [MZ]) co-twins may be temporal markers, that is, the "fossilized" evidence of various ischemic and other nongenetic insults that may have affected one fetus more than his MZ co-twin during that early part of the second trimester. In twins, prenatal insults (e.g., ischemia) frequently do not affect both co-twins to the same extent, so we examined seven putative markers of prenatal injury to the hand in 24 MZ twin pairs discordant for schizophrenia or delusional disorder. Compared with well co-twins, the affected co-twins had significantly higher total scores of fourth- and fifth-month dysmorphological hand anomalies.

Psychotic symptoms and suicidal behavior in hospitalized children.

Association of psychotic symptoms with suicidal behavior was studied in 90 hospitalized prepubertal children. Children with psychotic symptoms were more likely to have threatened or attempted suicide. The association of visual hallucinations with suicidal behavior was stronger than that of auditory hallucinations or psychotic ideation. The authors speculate that psychosis in general and visual hallucinations especially may be indicators of suicide risk among children.

A monozygotic mirror-image twin pair with discordant psychiatric illnesses: a neuropsychiatric and neurodevelopmental evaluation.

One piece of genetic evidence for the biological distinctness of schizophrenia and bipolar illness is the rarity of monozygotic twin pairs in which one twin suffers from schizophrenia and the other from bipolar disorder. The authors describe a pair of monozygotic mirror-image twins with discordant diagnoses, schizophrenia in one twin and bipolar or schizoaffective disorder in the other.

Prenatal growth markers in schizophrenia: a monozygotic co-twin control study.

OBJECTIVE: This co-twin study investigated monozygotic twins who were discordant for schizophrenia for evidence of prenatal growth differences between the affected and well co-twins. METHOD: Four dermatoglyphic markers of prenatal growth were obtained by established procedures from 26 monozygotic twin pairs discordant for schizophrenia, 13 monozygotic twin pairs concordant for schizophrenia, and several normal monozygotic twin samples. RESULTS: The a-b ridge count differences between the affected and well co-twins were greater than those found for concordant and normal monozygotic pairs. In comparison with their well co-twins, the affected twins, in discordant pairs, had developed fewer epidermal ridges in the a-b interdigital area of their right palms. In contrast, no significant differences were found between the affected twins and their well co-twins on markers associated with fetal development before 13 or after 15 weeks estimated gestational age. CONCLUSIONS: Because the a-b ridges are known to complete development between 13 and 15 weeks estimated gestational age, the results provide physical evidence suggesting that the schizophrenia-affected monozygotic twins alone experienced a time-specific and time-limited dysgenesis during this time. Commonalities in the ontogeny of epidermal and neurological structures are discussed.

Dyskinetic movements, cognitive impairment, and negative symptoms in elderly neuropsychiatric patients.

The presence or absence of tardive dyskinesia, cognitive status, and psychopathology were assessed in a group of elderly male psychiatric patients (N = 49) in a nursing home setting. Twenty-five patients were found to have tardive dyskinesia, which was associated with a greater degree of cognitive impairment and negative symptoms. This finding was not related to obvious macroscopic organic pathologies, which were less prevalent in the dyskinetic patients. In fact, patients with frontal lesions (primarily lobotomies) had a significantly lower prevalence of tardive dyskinesia.

High prevalence of visual hallucinations in research subjects with chronic schizophrenia.

The authors examined the prevalence of visual hallucinations in severely ill hospitalized research subjects with carefully diagnosed chronic schizophrenia and found it to be high. A chart review of 100 discharged subjects revealed documentation of visual hallucinations in 32%, and a prospective examination of 43 additional subjects revealed a history of visual hallucinations in 56% (N = 24). Also, the fact that in 43% of the patients with visual hallucinations the history of visual hallucinations was first documented during the research ward work-up suggests that clinicians frequently do not inquire about visual hallucinations in patients with chronic schizophrenia.

Second-trimester markers of fetal size in schizophrenia: a study of monozygotic twins.

OBJECTIVE: Since the second prenatal trimester is the critical period of massive neural cell migration to the cortex, and fingertip dermal cells migrate to form ridges during this same period, the authors sought to determine whether there are differences in fingertip ridge count in pairs of monozygotic twins discordant for schizophrenia, possibly indicating that a prenatal anatomical insult affected the twins differently. METHOD: The fingertip dermal ridges of 30 pairs of monozygotic twins (23 pairs in which the twins were discordant for schizophrenia and seven pairs in which both twins were normal) were counted by two persons trained in anthropometric research. Intrapair differences in the counts were then measured, and the differences among the pairs of normal twins were compared with the differences among the pairs discordant for schizophrenia. RESULTS: The twins discordant for schizophrenia had significantly greater absolute intrapair differences in total finger ridge count and significantly greater percent intrapair differences than the normal twins; i.e., their fingerprints were significantly less "twin-like." CONCLUSIONS: The study suggests that various second-trimester prenatal disturbances in the epigenesis of one twin in a pair discordant for schizophrenia may be related to the fact that only one of the twins expresses his or her genetic predisposition toward schizophrenia. This is consistent with a "two-strike" etiology of schizophrenia: a genetic diathesis plus a second-trimester environmental stressor.

Congenital dermatoglyphic malformations and psychosis: a twin study.

OBJECTIVE: In a previous twin study, congenital dermatoglyphic abnormalities, such as ridge dissociations and abnormalities of palmar flexion creases, were more prevalent in twins with psychotic and related disorders than in comparison twins. This study was an attempt to replicate that finding in an independent study group. METHOD: Ridge dissociations and abnormal palmar flexion creases were assessed in monozygotic pairs concordant (19 pairs) and discordant (31 pairs) for psychosis and related disorders. RESULTS: The presence of either ridge dissociations or abnormal palmar flexion creases was higher in the combined group of affected concordant and discordant twins (37.7%), than in the nonaffected discordant twins (20.0%; odds ratio=2.4). In the discordant pairs, the presence of either abnormality was strongly associated with psychotic disorder (odds ratio=3.0). CONCLUSIONS: Factors affecting early fetal development may increase the risk for psychotic disorder. Differential exposure to such early risk factors may contribute to twin discordance for psychotic disorder.

Correlation of severity of psychiatric patients' delusions with right hemispatial inattention (left-turning behavior).

Studies associate psychotic disorders with various forms of subtle inattention to the right hemispace (left-turning behavior). The authors examined the correlation between this dopamine-related sign and severity of delusions (presumably dopaminergic symptoms) in 20 psychotic patients. Delusions were significantly correlated with severity of left-turning bias, and this neurological sign accounted for 33% of the variance in severity of delusions.

Compound measure of hand-foot-eye preference masked opposite turning behavior in healthy right-handers and non-right-handers: technical comment on Mohr et al. (2003).

A previous article reported opposite turning behavior in right-handers and non-right-handers (C. Mohr. T. Landis, H. S. Bracha, & P. Brugger, 2003). This observation appears contradictory to the 1st study on long-term spontaneous turning behavior in healthy participants (H. S. Bracha, D. J. Seitz, J. Otemaa, & S. D. Click, 1987). These latter authors found a complex interaction between hemispheric dominance, preferred turning side, and sex. C. Mohr et al. (2003) argued that the differentiation of the population in hemisphere-dominant groups by a compound measure of hand-foot-eye preference might have masked their recent finding. Thus, this commentary presents a reanalysis of the original data set (H. S. Bracha et al., 1987). Replicating recent observation, right-handers preferred left-sided turns; and non-righthanders, right-sided turns. This replication strengthens the proposition that handedness and turning behavior might depend on interhemispheric dopamine asymmetries.

Opposite turning behavior in right-handers and non-right-handers suggests a link between handedness and cerebral dopamine asymmetries.

The strong right hand preference in humans remains a riddle; no lateralized behavior other than fine finger dexterity relates to it. The relation between handedness and language dominance may be far weaker than currently judged; after all, both right-handers and non-right-handers utilize the left brain for speech. There is, however, a lateralized motor preference in animals, turning behavior, that is strongly associated with hemispheric dopamine (DA) asymmetries. Turning consistently occurs towards the side with less DA. The authors tested 69 right-handers and 24 non-right-handers with a device recording spontaneous turning behavior for 20 hr within 3 days. Findings indicate that right-handers preferred left-sided turning and non-right-handers preferred right-sided turning. This result suggests a link between handedness and DA asymmetries.

Is there a right hemi-hyper-dopaminergic psychosis?

This selective review argues that a small subgroup among the patients meeting DSM-III-R criteria for schizophrenia appears to have an underlying right striatal hyper-dopaminergia. The subgroup is distinguished by a group of objective signs including: (1) asymmetric, usually right-sided, neuroleptic induced parkinsonian side effects; (2) asymmetric, usually left-sided, tardive dyskinesia; (3) a subclinical tendency to turn toward the left; (4) a subclinical right hemi-space sensory neglect; and (5) dopamine receptor densities greater in the right striatum than in the left.

Left turning (swivel) in manic patients.

Nineteen bipolar inpatients in manic episodes and 19 normal control subjects were tested on a two-button task which required turning (swiveling) 180 degrees to collect coin-reinforcers. Significantly more right-handed (8/16) manic patients turned left (consistently 16 times to collect reinforcement) than right-handed normal controls (1/15), most of whom turned consistently right 16 times. Right-handed manic patients were also significantly slower with both hands on a motor sequencing task (Pin Test) than the normal controls. Left hemi-spatial preference may be linked to asymmetric striatal dopaminergic activity common to all psychoses.

Racial differences in the diagnosis of psychosis.

In clinical populations, it has been reported that African-American patients are more likely to receive a diagnosis of schizophrenia than similar Caucasian patients. Factors contributing to this racial discrepancy are poorly defined. The authors examined the hypothesis that racial differences in severity of first-rank symptoms of schizophrenia contribute to this diagnostic difference. Patients were recruited as part of the DSM-IV Field Trial for Schizophrenia and Other Psychotic Disorders, and evaluated using a structured rating instrument. Symptom and diagnostic comparisons were performed between black and white patients. Black patients were significantly more likely than white patients to be diagnosed with schizophrenia and less likely with psychotic depression. Racial differences in symptom profiles were observed with black patients demonstrating more severe psychotic symptoms, in general, and first-rank symptoms, specifically. There were no racial differences in rates of affective syndromes or severity of affective symptoms. Racial disparity in diagnosis of psychotic patients may be in part secondary to more severe first-rank symptoms in black patients, causing clinicians to stray from DSM-III-R criteria.

Season of birth and neurodevelopmental disorders: summer birth is associated with dyslexia.

OBJECTIVE: Increased risk for certain psychiatric disorders has been associated with season of birth. This study was undertaken to look for hypothesized season-of-birth effects for dyslexia, schizophrenia spectrum disorders, and neurological soft signs in children and adolescents. METHOD: Month of birth and the diagnostic findings in question were examined based on charts from a clinic population of 585 boys. Odds ratios and etiological fractions were calculated. RESULTS: Neurological soft signs showed a sporadic peak for June births and schizophrenia spectrum showed a peak for August and November. A smooth curve suggesting true seasonality was evident in dyslexia for births in May, June, and July. For different 5-year birth cohorts, early summer birth accounts for 24 to 71% of cases of dyslexia. CONCLUSIONS: The authors suggest that viral infection, especially influenza, during the second trimester of pregnancy is the most attractive hypothesis to explain these findings. If this hypothesis is supported, immunization in women of child-bearing age could reduce the incidence of dyslexia. Secondary prevention could also be enhanced by early identification and treatment of children who were exposed in utero.