First-episode schizophrenic psychosis differs from first-episode affective psychosis and controls in P300 amplitude over left temporal lobe.

BACKGROUND: Schizophrenia is associated with central (sagittal) midline reductions of the P300 cognitive event-related potential and topographic asymmetry of P300, with reduced left temporal voltage. This P300 asymmetry is, in turn, linked to tissue volume asymmetry in the posterior superior temporal gyrus. However, it is unknown whether P300 asymmetry is specific to schizophrenia and whether central and lateral P300 abnormalities are due to chronic morbidity, neuroleptic medication, and/or hospitalization, or whether they are present at the onset of illness. METHODS: P300 was recorded in first-episode schizophrenia, first-episode affective psychosis, and control subjects (n = 14 per group). Subjects silently counted rare (15%) target tones (1.5 kHz) among trains of standard tones (1.0 kHz). Averages were constructed from brain responses to target tones. RESULTS: Peak amplitude of P300 and integrated voltage over 300 to 400 milliseconds were significantly different between first-episode schizophrenics and controls over the posterior sagittal midline of the head. First-episode schizophrenics displayed smaller amplitudes over the left temporal lobe than first-episode affective psychotics and controls, but the groups showed no differences over the right temporal lobe. CONCLUSIONS: Left-sided P300 abnormality in first-episode schizophrenia relative to first-episode affective psychosis and controls suggests that P300 asymmetry is specific to schizophrenic psychosis and present at initial hospitalization. This P300 asymmetry suggests left temporal lobe dysfunction at the onset of schizophrenia.

Neurological "hard" signs and family history of psychosis in schizophrenia.

Previous research found schizophrenics to have significantly more neurological signs than normal controls, even when signs were screened to exclude possible artifacts, and limited to "hard" signs of localizing significance. Schizophrenics with a family history of psychosis also tended to have more neurological signs than those without such a history. The present study examined whether these findings could be confirmed in new samples of schizophrenics and controls, using interview-based DSM-III and DSM-III-R diagnoses. Schizophrenics had significantly more hard signs than controls, and schizophrenics with a family history for psychosis again had more signs than those without this history. When present study data were analyzed alone, as well as when pooled with data from previous research using similar methods, hard signs were significantly greater in both (a) schizophrenics versus controls and (b) schizophrenics with versus without a family history of psychosis, supporting the hypothesis that neurological signs reflect a significant etiologic factor in schizophrenia.

Frontal brain volume and context effects in short-term recall in schizophrenia.

In a group of schizophrenic patients, magnetic resonance imaging (MRI) measures of relative frontal brain volume (total frontal volume/total cerebral volume) correlated highly with the capacity to use context as an aid to recall in a verbal memory task. The dorsolateral area of the prefrontal cortex appears to have contributed most to this effect. Recall of simple word lists without contextual features revealed no correlation with relative frontal volume. With increasing contextual organization of the material, correlations between frontal volume and recall scores increased significantly. These findings are consistent with the general proposition that impairment in the use of informational redundancy is a significant component of schizophrenic pathology.

Neuroimaging in bipolar disorder: what have we learned?

New technologies are offering increasingly powerful means to obtain structural, chemical, and functional images of the brain during life, often without the use of ionizing radiation. Bipolar disorder, with its clear physiologic features, would appear to be a prime candidate for the application of current brain imaging; however, only a modest number of studies have been reported to date, and most studies have small sample sizes and heterogeneous subject groups. Nonetheless, there are a few consistent findings among these studies, including the following: 1) Structural imaging studies suggest an increased number of white matter hyperintensities in patients with bipolar disorder. These may be lesions unique to bipolar disorder and its treatment, or related to cardiovascular risk factors, which are more common in bipolar patients. Decreased cerebellar size and anomalies of cerebellar blood volume have also been reported. Increased sulcal prominence and enlargement of the lateral and third ventricles are less consistently observed findings. 2) Spectroscopic imaging suggests abnormalities of metabolism of choline-containing compounds in symptomatically ill bipolar patients and, possibly, treatment-induced changes in choline- and myoinositol-containing compounds. Each of these groups of metabolites serves as a component of membrane phospholipids and cellular second-messenger cycles. 3) Metabolic and blood flow studies provide evidence for decreased activity of the prefrontal cortex (PFC) in bipolar patients during depression. It is not clear if these changes are restricted to particular subregions of the PFC, nor if they are reversed with mania. No single pathophysiologic mechanism yet explains these findings, although all might be due to regional alterations in cellular activity and metabolism or changes in cell membrane composition and turnover. The development of imaging technologies has far outpaced their use in bipolar disorder. The promise of future studies is great, with more powerful magnetic resonance scanners, additional ligands for positron emission tomography and single photon emission computed tomography imaging, and improved image generation and processing already available.

Hemispheric asymmetry of frontal and temporal gray matter and age of onset in schizophrenia.

BACKGROUND: Investigators have reported lack of normal asymmetry of lateralization in some schizophrenic patients, as measured postmortem and by preference and/or performance. It has been suggested that this lack of asymmetry is related to early onset of schizophrenia. The present study extends the inquiry by magnetic resonance imaging (MRI) measurement of volumetric asymmetry. METHODS: Hemispheric asymmetry of volume in regional gray matter was examined in 16 schizophrenic patients who had undergone MRI of brain volume. RESULTS: Low levels of hemispheric asymmetry in the frontal and temporal areas were strongly associated with early onset of schizophrenia, the association with frontal volume being more marked than with temporal volume. No relationship was found in the other brain areas that were scanned. The findings were not artifacts of chronological age, nor of extreme scores in a small sample. CONCLUSIONS: These findings are consistent with the hypothesis that failure to develop asymmetry is an important component of the pathology underlying some forms of schizophrenia.

Hippocampal volume in primary unipolar major depression: a magnetic resonance imaging study.

BACKGROUND: Previous studies have shown that major depression is frequently accompanied by hypercortisolemia. There is some evidence suggesting that an increase in the glucocorticoid levels may make hippocampal cells more vulnerable to insults caused by hypoxia, hypoglycemia, or excitatory neurotransmitters. Using magnetic resonance imaging (MRI), the hippocampi of patients with major depression were measured and compared with values observed in control subjects. METHODS: Thirty-eight patients with primary unipolar major depression were recruited. Twenty control subjects were matched for age, gender, and years of education. The hippocampal volume was measured from coronal MRI scans in all of the subjects. Patients were also grouped and compared as responders and nonresponders to treatment with fluoxetine of 20 mg/day, for 8 weeks. Hamilton Depression Rating Scale (HDRS) was used to determine the severity of depression. RESULTS: No significant differences were observed between the hippocampal volumes of patients with major depression and control subjects; however, a significant correlation was observed between the left hippocampal volume of men and their HDRS baseline values. In addition, female responders had a statistically significant higher mean right hippocampal volume than nonresponders. CONCLUSIONS: The results of our study indicate no reduction in the volume of the hippocampus in patients with major depression. Nonetheless, the results do suggest that the effects of disease severity, gender, and treatment response may influence hippocampal volume.

A quantitative magnetic resonance imaging study of cerebral and cerebellar gray matter volume in primary unipolar major depression: relationship to treatment response and clinical severity.

The authors investigated whether there were differences in cerebral and cerebellar gray and white matter volumes in depressed patients compared to controls, and whether this was associated with treatment response to fluoxetine. Brain magnetic resonance images were obtained from 38 unipolar depressed patients and 20 age, gender, and educationally matched comparison subjects. Patients were divided into groups of "responders" and "nonresponders" based on change in 17-item Hamilton Depression Rating Scale (HDRS) after an 8-week standardized trial of fluoxetine, 20 mg/day. There were no group mean differences in cerebral or cerebellar tissue volumes between patients and controls, or responders and nonresponders. For nonresponders to fluoxetine treatment, cerebral and cerebellar gray matter volume, and total cerebellar tissue volume decreased as baseline HDRS increased. The results suggest an association between gray matter volume and severity of illness in nonresponders to fluoxetine treatment.

Increased orbitofrontal cortex levels of choline in depressed adolescents as detected by in vivo proton magnetic resonance spectroscopy.

BACKGROUND: The frontal lobe has been implicated in the pathology of depression in adults. Through the use of magnetic resonance spectroscopy, altered brain choline levels have also been linked to the pathophysiology of affective disorders. METHODS: To identify possible alterations in orbitofrontal cortex levels of cytosolic choline in adolescents with and without depression, 22 depressed and 43 control adolescents were recruited. Of those recruited, usable proton magnetic resonance spectra were acquired from a voxel in the left anterior medial frontal lobe of 17 depressed (mean age 15.8+/-1.6) and 28 healthy adolescents (mean age 14.5+/-1.7). RESULTS: Orbitofrontal cytosolic choline/creatine (Cho/Cr) ratios (p =.032) and cytosolic choline/N-acetyl aspartate (Cho/NAA) ratios (p =.043) were significantly higher in the depressed subjects than in the control subjects. There were no significant differences between depressed and control subjects in gray or white matter content within the voxel. CONCLUSIONS: These findings suggest that brain cytosolic choline may be increased in depressed adolescents in comparison with control subjects and independent of a corresponding structural change. These results are consistent with similar, previously reported findings in adults and suggest that depression in adolescents is associated with alterations in orbitofrontal metabolism.

Basal ganglia choline levels in depression and response to fluoxetine treatment: an in vivo proton magnetic resonance spectroscopy study.

We have investigated proton magnetic resonance spectra of the basal ganglia in 41 medication-free outpatients with major depression, prior to starting an 8-week standardized trial of open-label fluoxetine, and 22 matched comparison subjects. Upon completing the trial, depressed subjects were classified as treatment responders (n = 18) or nonresponders (n = 23), based on changes in the Hamilton Depression Rating Scale. Depressed subjects had a lower area ratio of the choline resonance to the creatine resonance (Cho/Cr) than comparison subjects. This statistically significant difference between the depressed subjects and comparison subjects was more pronounced in the treatment responders than in the nonresponders. There were no differences in the relative volumes of gray matter or white matter in the voxel used for proton spectroscopy in depressed subjects relative to comparison subjects. These results are consistent with an alteration in the metabolism of cytosolic choline compounds in the basal ganglia of depressed subjects and, in particular, those who are responsive to fluoxetine.

Greater hemodynamic response to photic stimulation in schizophrenic patients: an echo planar MRI study.

Functional echo planar magnetic resonance imaging (MRI) probably will be of importance in assessing brain abnormalities in psychiatric disorders. The authors used functional MRI to measure the relative magnitude of the change in image signal intensity, reflecting changes in regional neuronal activity caused by photic stimulation, in eight patients with schizophrenia and nine normal comparison subjects. The mean signal intensity change in the primary visual cortex was significantly greater in patients with schizophrenia (mean = 4.6%, SD = 1.5%) than in normal comparison subjects (mean = 3.1%, SD = 1.3%). These results may reflect a variety of factors, including diffuse structural brain changes as well as primary or iatrogenic impairment of mitochondrial function or energy metabolism.

Morphometry of individual cerebellar lobules in schizophrenia.

OBJECTIVE: Previous imaging studies have described focal cortical changes in schizophrenia, with predominant findings of abnormalities in the temporal and frontal regions. The current study hypothesized that cerebellar regions involved in feedback and feed-forward loops with cortical regions affected in schizophrenia would also demonstrate structural changes. METHOD: Using magnetic resonance imaging, the authors measured the volume of individual cerebellar lobules in 19 patients with schizophrenia and 19 healthy comparison subjects. RESULTS: The inferior vermis was significantly smaller in the schizophrenic group than in the comparison group. Patients with schizophrenia also demonstrated a significantly smaller cerebellar asymmetry than the comparison subjects. CONCLUSIONS: The authors hypothesize that these morphometric changes may be developmental in origin and possibly related to cortical abnormalities.

Temporal lobe proton magnetic resonance spectroscopy of patients with first-episode psychosis.

OBJECTIVE: The authors measured the ratio of N-acetyl aspartate (a putative neuronal marker) to creatine-phosphocreatine in patients with first-episode psychosis by using proton magnetic resonance spectroscopy (MRS). METHOD: Temporal lobe 1H MRS was performed bilaterally on 13 patients with first-episode psychosis and 15 comparison subjects. The N-acetyl aspartate/creatine-phosphocreatine and choline/creatine-phosphocreatine ratios were determined. RESULTS: The N-acetyl aspartate/creatine-phosphocreatine ratio of the psychotic patients was significantly lower than that of the comparison subjects. CONCLUSIONS: These preliminary data suggest that abnormalities in temporal lobe N-acetyl aspartate concentration are present early in psychotic illness.

Inverse relationship of perinatal complications and eye tracking dysfunction in relatives of patients with schizophrenia: evidence for a two-factor model.

OBJECTIVE: Because both smooth pursuit eye tracking dysfunction and obstetrical complications are significant risk factors for schizophrenia, the authors tested the predictions of a two-factor model of how eye tracking dysfunction and obstetrical complications covary in patients with schizophrenia, their siblings, and comparison subjects. METHOD: Psychiatric diagnoses, eye tracking dysfunction, and obstetrical complications noted in birth records were independently assessed in 18 patients with schizophrenia, 16 of their siblings without schizophrenia, and 49 comparison subjects with neither personal nor family histories of schizophrenia. RESULTS: As hypothesized, 1) the combination of eye tracking dysfunction and perinatal obstetrical complications discriminated patients with schizophrenia significantly from subjects without schizophrenia, including siblings of patients with schizophrenia, and 2) eye tracking dysfunction and perinatal obstetrical complications manifested a significant inverse association in the nonschizophrenic siblings of patients with schizophrenia. CONCLUSIONS: These results support a two-factor model in which obstetrical complications often interact with genetic liability, indicated by eye tracking dysfunction, to produce schizophrenia.

Functional magnetic resonance imaging of schizophrenic patients and comparison subjects during word production.

OBJECTIVE: This study was undertaken to test the feasibility of using functional magnetic resonance imaging (MRI) to examine changes in cortical activation in response to verbal tasks in two brain regions. METHOD: Twelve schizophrenic patients and 11 comparison subjects underwent functional MRI of the frontal and temporal lobes. Stimulus sequences were divided into five 30-second segments by using a task-activation paradigm that alternated between resting and stimulated states. Functional images were collected every 30 seconds by using a gradient echo pulse sequence. RESULTS: Schizophrenic subjects demonstrated significantly less left frontal activation and greater left temporal activation than comparison subjects during a word fluency task. CONCLUSIONS: These preliminary data suggest that functional MRI has the sensitivity to detect differences in activation between comparison subjects and schizophrenic patients during higher cortical functions. These findings are in agreement with PET studies that reported reduced left frontal activation during challenge paradigms for the schizophrenic patients.

Dynamic susceptibility contrast MRI of regional cerebral blood volume in Alzheimer's disease.

OBJECTIVE: The purpose of this study was to investigate the potential effectiveness of dynamic susceptibility contrast magnetic resonance imaging (MRI) to discriminate elderly patients with Alzheimer's disease from normal matched comparison subjects. METHOD: Images of regional cerebral blood volume (CBV) were generated from echo-planar MRI with the dynamic susceptibility contrast method in 13 Alzheimer's disease patients and 13 comparison subjects group-matched on age and gender. RESULTS: Temporoparietal cerebral blood volume, expressed as a percentage of the cerebellum value, was reduced 17% bilaterally in the patients with Alzheimer's disease. Blood volume in sensorimotor regions was reduced only 8.5% in the patients. Discriminant function analysis based on left and right temporoparietal measures correctly classified 88.5% of the subjects as patients or comparison subjects. Temporoparietal CBV was reduced even in mildly affected Alzheimer's disease patients (Mini-Mental State scores > 24). CONCLUSIONS: Dynamic susceptibility contrast MRI of regional CBV is promising as a nonradioactive, potentially lower-cost alternative to other functional neuroimaging methods for evaluating Alzheimer's disease.

Age-related reduction in functional MRI response to photic stimulation.

Many functional imaging studies have demonstrated age-related alterations in cerebral blood flow during the resting state. However, few studies have addressed possible differences in functional response to cerebral activation. We assessed the response of visual cortex to photic stimulation in 9 normal elderly subjects and 17 normal younger subjects with blood oxygenation level dependent functional magnetic resonance imaging. We found that the amplitude of response in elderly subjects was significantly decreased compared to younger subjects (2.5 +/- 1.0% versus 4.0 +/- 1.6%, p = 0.01), suggesting a reduction in functional activation or an age-related alteration in the coupling of blood oxygenation to focal activation.

The neuronal architecture of the anteroventral cochlear nucleus of the cat in the region of the cochlear nerve root: horseradish peroxidase labelling of identified cell types.

Golgi impregnations of the posterior part of the cat's anteroventral cochlear nucleus have revealed two types of neurons, bushy cells with short bush-like dendrites and stellate cells with long, tapered processes; Nissl stains have revealed globular and multipolar cell bodies with dispersed and clumped ribosomal patterns, respectively. In the present study, we injected horseradish peroxidase into the trapezoid body. Ipsilaterally, retrograde, diffuse labelling of neurons, presumably through damaged fibers, yielded Golgi-like profiles of numerous bushy cells with typical dendrites and with thick axons projecting toward the trapezoid body. Stellate cells were almost never labelled in this way. Anterograde diffuse labelling of thick axons demonstrated calyx endings in the contralateral medial nucleus of the trapezoid body. In the electron-microscope, the perikarya of diffusely-filled bushy neurons were found to have the dispersed ribosomal pattern and the kinds of synaptic endings typical of globular cells, including large profiles of end-bulbs from cochlear nerve axons. After injections restricted to the medial trapezoid nucleus, granularly-labelled cells in the cochlear nucleus were almost completely confined to the contralateral side; Nissl counterstaining showed them to be globular cells in the posterior part of the anteroventral cochlear nucleus. After larger injections, involving surrounding regions of the superior olivary complex, granular labelling occurred throughout the ventral cochlear nucleus on both sides. There is also evidence that stellate cells in Golgi impregnations correspond to multipolar cell bodies in Nissl stains. We conclude that bushy cells typically correspond to globular cells, which receive end-bulbs from the cochlea and send thick axons to the contralateral medial trapezoid nucleus, where they form calyces on principal cells. Principal cells, in turn, are known to project to the lateral superior olive and to one of the nuclei of origin of the crossed olivo-cochlear bundle, which feeds back to the cochlea. In this circuit, correlations between synaptic patterns and particular physiological signal transfer characteristics can be suggested. These could be related to binaural intensity interactions in the lateral superior olive and to a regulatory loop involving the olivo-cochlear bundles.

Chronic citicoline increases phosphodiesters in the brains of healthy older subjects: an in vivo phosphorus magnetic resonance spectroscopy study.

RATIONALE: Phosphatidylcholine (PtdCho) in brain cell membranes decreases with age. Evidence from both animal and in vitro studies indicates that CDP-choline (citicoline) administration may increase phosphatidylcholine (PtdCho) synthesis and might reverse PtdCho loss. OBJECTIVES: We investigated whether oral citicoline can increase PtdCho synthesis in the brains of older subjects by measuring levels of phosphorus-containing metabolites using proton-decoupled phosphorus magnetic resonance spectroscopy ((31)P-MRS) before and after citicoline treatment. METHODS: All subjects took 500 mg citicoline once orally each day for 6 weeks, then took either citicoline or placebo once orally per day for a second 6-week period. Subjects underwent a (31)P-MRS scan at baseline and following 6 and 12 weeks of treatment. RESULTS: Treatment with citicoline for 6 weeks was associated with a 7.3% increase from baseline levels in brain phosphodiesters ( P=0.008), including an 11.6% increase in glycerophosphoethanolamine ( P=0.002) and a 5.1% increase in glycerophosphocholine ( P=0.137). Subjects who continued to take citicoline for the second 6-week period did not show significant additional increases in the levels of these metabolites. No changes were seen in other phosphorus-containing metabolites. There was a correlation between improvement on the California Verbal Learning Test and increase in phosphodiesters. CONCLUSIONS: The increases in phosphodiesters seen in this study indicate that phospholipid synthesis and turnover were stimulated by 6 weeks of oral citicoline. These results in humans support previous in vitro and animal studies and suggest that the administration of oral citicoline may be of use in reversing age-related changes in the brain.

Neurologic signs of cerebellar and cortical sensory dysfunction in schizophrenics and their relatives.

Previous research has found that both schizophrenics and their relatives have significantly elevated rates of clinical neurologic signs--including 'hard' signs screened to exclude artifacts. The present study examined whether hard signs that indicate relatively localized dysfunction in particular brain regions significantly distinguish schizophrenics and/or their non-schizophrenic relatives from psychiatrically normal controls and patients with other disorders. All patients were diagnosed with DSM-III or DSM-IIIR criteria, using information from structured interviews, supplemented by chart review and family informants. Subjects were administered clinical neurologic examinations by a neurologist blind to diagnosis. The proband sample, composed of 54 schizophrenic or schizoaffective subjects, had a significantly greater proportion of subjects with signs of cerebellar dysfunction than any of the comparison samples, which included: 44 control subjects, 24 patients with substance abuse, 37 patients with bipolar disorder, and 73 of the probands' non-schizophrenic parents and adult siblings. Proportions of both probands and their relatives with signs of dysfunction of sensory cortex were significantly higher than for other groups. Cerebellar and sensory cortical dysfunctions may distinguish different subgroups of schizophrenics and may tend to reflect, respectively, non-familial and familial neuropathological factors.

Obstetrical complications and trail making deficits discriminate schizophrenics from unaffected siblings and controls.

Numerous studies have reported that both obstetrical complications (OCs) and deficits on the Trail Making Test show elevated prevalences in schizophrenics. Trail Making deficits have also been reported to be more common in schizophrenics' relatives than in controls, suggesting poor Trail Making performance may be a behavioral indicator of a familial risk factor for schizophrenia. Few studies, however, have investigated how these two variables co-vary in samples of schizophrenics and non-schizophrenics. In this study, DSM-III-R diagnoses, OCs noted in birth records, and Trail Making performance were independently assessed in 30 subjects: 9 schizophrenics, 8 of their non-schizophrenic siblings, and 13 comparison subjects with neither a personal nor a family history of schizophrenia. Results supported two key predictions of a two-factor etiologic model of schizophrenia: (a) the combination of perinatal OCs and poor Trail Making performance discriminated schizophrenics extremely well from non-schizophrenics, including their own non-schizophrenic sibs, and (b) perinatal OCs and Trail Making errors manifested a significant inverse association among schizophrenics' non-schizophrenic sibs, but not among other subjects.