Gender differences and similarities in aggression, suicidal behaviour, and psychiatric comorbidity in borderline personality disorder.

OBJECTIVE: We examined gender differences and similarities in aggression, impulsivity, suicidal behaviour, and psychiatric comorbidity in men and women with borderline personality disorder (BPD) compared with healthy controls. METHOD: A community sample of 511 participants (healthy controls: 81 men and 82 women; BPD patients: 145 men and 203 women) were rigorously characterized using structured diagnostic interviews and symptom severity assessments. RESULTS: In comparison with women with BPD, men were less educated, had higher total Barratt Impulsivity Scale (BIS), BIS-motoric impulsiveness and BIS-non-planning impulsiveness subscale, total Buss-Perry Aggression Questionnaire (BPAQ), and BPAQ-physical aggression subscale scores. Men with BPD were more likely to have comorbid narcissistic, antisocial, paranoid, and schizotypal personality disorders, alcohol and substance use disorders but less likely to have dependent and obsessive-compulsive personality disorders compared to women with BPD. There was a trend toward higher maximum lethality of suicide attempts in men suicide attempters compared with women suicide attempters but no difference between men and women with regard to the proportion of suicide attempters or the number of suicide attempts. CONCLUSION: Men with BPD are more impaired and may be at higher risk of dying by suicide compared to women with BPD.

Severe childhood trauma and clinical and neurocognitive features in schizotypal personality disorder.

OBJECTIVE: Literature suggests that childhood trauma increases vulnerability for schizophrenia-spectrum disorders, including schizotypal personality disorder (SPD). Yet, it remains unexplored whether childhood trauma predicts symptom load and the level of neurocognitive functioning in SPD. METHOD: We included 225 individuals with SPD and 127 healthy controls. Childhood trauma was evaluated using the Childhood Trauma Questionnaire, and schizotypal traits were assessed using the Schizotypal Personality Questionnaire. Standard neurocognitive assessments covered six cognitive domains. RESULTS: All types of reported childhood trauma were significantly associated with SPD, in a linear fashion. Severe sexual abuse showed the greatest magnitude of association with higher cognitive-perceptual load (e.g., ideas of reference, odd belief or magical thinking); severe emotional neglect was associated with interpersonal scores (e.g., excessive social anxiety, constricted affect) within the SPD group. SPD individuals who reported severe trauma showed worse cognitive functioning (i.e., working memory, verbal/visual learning and memory, as well as verbal fluency). CONCLUSIONS: Particular severe childhood trauma types were associated with higher cognitive-perceptual and interpersonal symptoms in SPD, along with worse cognitive functioning. These findings highlight the need for clinicians to enquire about childhood trauma in SPD patients, since unaddressed early adverse experiences may carry long-term negative consequences.

Magnetic resonance imaging of the thalamic mediodorsal nucleus and pulvinar in schizophrenia and schizotypal personality disorder.

BACKGROUND: The importance of neuronal interactions in development, the cortical dependence of many thalamic nuclei, and the phenomenon of transsynaptic degeneration suggest possible abnormalities in thalamic nuclei with connections to other brain regions implicated in schizophrenia. Because frontal and temporal lobe volumes are diminished in schizophrenia, volume loss could characterize their primary thalamic relay nuclei (mediodorsal nucleus [MDN] and pulvinar). METHODS: Tracers delineated the thalamus, MDN, and pulvinar on contiguous 1.2-mm magnetic resonance images in 12 schizophrenic patients, 12 with schizotypal personality disorder (SPD), and 12 normal control subjects. The MDN and pulvinar were rendered visible by means of a Sobel intensity-gradient filter. RESULTS: Pixel overlap for delineation of all structures by independent tracers was at least 80%; intraclass correlations were r = 0.78 for MDN and r = 0.83 for pulvinar. Pulvinar volume was smaller in schizophrenic (1.22 +/- 0.24 cm(3)) and SPD (1.20 +/- 0.23 cm(3)) patients than controls (1.37 +/- 0.25 cm(3)). Differences for MDN were not statistically significant; however, when expressed as percentage of total brain volume, pulvinar and MDN together were reduced in SPD (0.14%) and schizophrenic (0.15%) patients vs controls (0.16%). Reductions were more prominent in the left hemisphere, with MDN reduced only in the schizophrenic group, and pulvinar in both patient groups. Total thalamic volume did not differ among the 3 groups. CONCLUSIONS: Measurement of MDN and pulvinar in magnetic resonance images is feasible and reproducible. Schizophrenic and SPD patients have volume reduction in the pulvinar, but only schizophrenic patients show reduction relative to brain volume in MDN.

Striatal size and relative glucose metabolic rate in schizotypal personality disorder and schizophrenia.

BACKGROUND: Schizotypal personality disorder (SPD) shares social deficits and cognitive impairment with schizophrenia, but is not typically characterized by frank psychosis. Because striatal size and functional activity have both been shown to be associated with psychotic symptoms, we carried out the first study of SPD to assess the caudate and putamen for comparison with findings in schizophrenia. METHODS: Patients with SPD (n = 16), schizophrenic patients (n = 42), and age- and sex-matched normal control subjects (n = 47) were assessed with magnetic resonance imaging. All of the patients with SPD and subsamples of the schizophrenic patients (n = 27) and control subjects (n = 32) were also assessed with positron emission tomography using fluorodeoxyglucose F-18. RESULTS: The relative size of the putamen in controls was significantly larger than in patients with SPD and significantly smaller than in schizophrenic patients, while the relative size of the caudate was similar in all 3 groups. Compared with control values, relative glucose metabolic rate in the ventral putamen was significantly elevated in patients with SPD and reduced in schizophrenic patients. When subsamples of schizophrenic patients (n = 10) and patients with SPD (n = 10) both of whom never received medication were compared, this pattern was more marked, with the highest value for the putamen being found in patients with SPD for the ventral slice and the lowest value for the right dorsal putamen. CONCLUSIONS: Patients with SPD showed reduced volume and elevated relative glucose metabolic rate of the putamen compared with both schizophrenic patients and controls. These alterations in volume and activity may be related to the sparing of patients with SPD from frank psychosis.

Dorsal striatal size, shape, and metabolic rate in never-medicated and previously medicated schizophrenics performing a verbal learning task.

BACKGROUND: Magnetic resonance imaging and positron emission tomography were used to study the size and metabolic rate of the caudate and the putamen in 18 patients with schizophrenia (n=16) or schizo-affective disorder (n=2) and 24 age- and sex-matched control subjects. METHODS: The patients were either never medicated (n=7) or drug free (n=11) for a median of 3 weeks. During uptake of fludeoxyglucose F 18, all patients performed a serial verbal learning test. Positron emission tomographic and magnetic resonance imaging scans were coregistered, and the caudate and the putamen were traced on the magnetic resonance image. RESULTS: The striatum had a significantly lower relative metabolic rate in schizophrenics than in controls. Never-medicated patients had lower metabolic rates in the right putamen (ventral part of the dorsal striatum) than previously medicated patients. The caudate was significantly smaller in never-medicated patients than in controls and largest in previously medicated patients. Patients with higher relative metabolic rates in the putamen scored higher on the Abnormal Involuntary Movements Scale. CONCLUSIONS: The findings are consistent with reports of striatal enlargement in previously medicated patients and size increases after neuroleptic treatment. Never-medicated patients, in contrast, had ventral striatal structures that were smaller and less active than those observed in controls and previously medicated patients.

Thalamic activation during an attention-to-prepulse startle modification paradigm: a functional MRI study.

BACKGROUND: Prepulse inhibition (PPI) of the startle reflex reflects early stages of information processing and is modulated by selective attention. Animal models indicate medial frontal-thalamic circuitry is important in PPI modulation. We report data from the first functional magnetic resonance imaging (fMRI) study examining whether attending to or ignoring a prepulse differentially activates brain areas within this circuitry. METHODS: Ten healthy subjects received structural and functional MRI. During fMRI acquisition, subjects heard intermixed attended and ignored tones serving as prepulses to the startle stimulus. Regions of interest were traced on structural MRI and coregistered to fMRI images. RESULTS: Greater amplitude fMRI blood-oxygen-level-dependent response to attended than ignored PPI conditions occurred in the right thalamus, and bilaterally in the anterior and mediodorsal thalamic nuclei, whereas the startle-alone condition showed deactivation. In transitional medial cortex (Brodmann Area 32), which is involved in affective processing of noxious stimuli, the startle-alone condition elicited the greatest response, the attended-PPI condition showed the smallest response, and the ignored-PPI condition was intermediate. CONCLUSIONS: These findings extend animal models to humans by indicating thalamic involvement in the modulation of PPI. Further fMRI investigations may elucidate other key structures in the circuitry underlying normal and disordered modulation of PPI.

Patterns of cortical activity and memory performance in Alzheimer's disease.

BACKGROUND: Declarative memory changes are the hallmark of Alzheimer's disease, although their functional neuroanatomy is not restricted to a single structure. Factor analysis provides statistical methods for evaluating patterns of cerebral changes in regional glucose uptake. METHODS: Thirty-three Alzheimer's patients and 33 age- and gender-matched control subjects were studied with magnetic resonance imaging and positron emission tomography with [(18)F] deoxyglucose. During the tracer-uptake period, subjects performed a serial verbal learning task. Cortical activity was measured in 32 regions of interest, four in each lobe on both hemispheres. RESULTS: Factor analysis with varimax rotation identified seven factors explaining 80% of the variance ("parietal cortex," "occipital cortex," "right temporo-prefrontal areas," "frontal cortex," "motor strip," "left temporal cortex," and "posterior temporal cortex"). Relative to control subjects, Alzheimer's patients showed significantly reduced values on the factors occipital cortex, right temporo-prefrontal areas, frontal cortex, and left temporal cortex. The factor temporo-prefrontal areas showed large differences between patients with good and poor performance, but little difference when control subjects were similarly divided. CONCLUSIONS: Findings suggest that Alzheimer's disease is characterized by altered patterns of cortical activity, rather than deficits in a single location, and emphasize the importance of right temporo-prefrontal circuitry for understanding memory deficits.

Age-related shift in brain region activity during successful memory performance.

Coregistered positron emission tomography (PET)/magnetic resonance imaging (MRI) was used to characterize brain function in 70 volunteers, aged 20-87 years, during a verbal memory task. Frontal activity showed an age-related decline that remained significant after statistical control for sulcal atrophy. Analyses of young and old subgroups matched for memory scores revealed that young good performers activated frontal regions, whereas old good performers relied on occipital regions. Although activating different cortical regions, good performers of all ages used the same cognitive strategy semantic clustering. Age-related functional change may reflect dynamic re-allocation in a network of brain areas, not merely anatomically fixed neuronal loss or diminished capacity to perform.

Feeling unreal: a PET study of depersonalization disorder.

OBJECTIVE: The goal of this study was to assess brain glucose metabolism and its relationship to dissociation measures and clinical symptoms in DSM-IV depersonalization disorder. METHOD: Positron emission tomography scans coregistered with magnetic resonance images of eight subjects with depersonalization disorder were compared to those of 24 healthy comparison subjects. The two groups did not differ in age, sex, education, performance on a baseline neuropsychological battery, or performance on a verbal learning task administered during [(18)F]fluorodeoxyglucose uptake. A cortical analysis by individual Brodmann's areas was performed. RESULTS: Compared to the healthy subjects, subjects with depersonalization disorder showed significantly lower metabolic activity in right Brodmann's areas 22 and 21 of the superior and middle temporal gyri and had significantly higher metabolism in parietal Brodmann's areas 7B and 39 and left occipital Brodmann's area 19. Dissociation and depersonalization scores among the subjects with depersonalization disorder were significantly positively correlated with metabolic activity in area 7B. CONCLUSIONS: Depersonalization appears to be associated with functional abnormalities along sequential hierarchical areas, secondary and cross-modal, of the sensory cortex (visual, auditory, and somatosensory), as well as areas responsible for an integrated body schema. These findings are in good agreement with the phenomenological conceptualization of depersonalization as a dissociation of perceptions as well as with the subjective symptoms of depersonalization disorder.

Decreased anterior cingulate gyrus metabolic rate in schizophrenia.

OBJECTIVE: This study examined glucose metabolism in the anterior and posterior cingulate cortex in schizophrenia. METHOD: Fifty unmedicated male schizophrenic patients and 24 normal men were studied with positron emission tomography. RESULTS: Compared with the normal men, the schizophrenic patients had lower relative metabolic rates in the anterior cingulate and higher rates in the posterior cingulate. CONCLUSIONS: The findings suggest hypofunction in the anterior cingulate cortex in schizophrenia.

Three-dimensional analysis with MRI and PET of the size, shape, and function of the thalamus in the schizophrenia spectrum.

OBJECTIVE: In an exploration of the schizophrenia spectrum, the authors compared thalamic size, shape, and metabolic activity in unmedicated patients with schizophrenia and schizotypal personality disorder to findings in age- and sex-matched healthy control subjects. METHOD: Coregistered magnetic resonance imaging (MRI) and positron emission tomography scans were obtained in 27 schizophrenic patients, 13 patients with schizotypal personality disorder, and 32 control subjects who performed a serial verbal learning test during tracer uptake. After thalamus edges were outlined on 1.2-mm MRI scans, a radial warping program yielded significance probability mapping in three dimensions. RESULTS: Significance probability mapping (with resampling) identified an area in the region of the mediodorsal nucleus bilaterally with significantly lower relative metabolism in the schizophrenia group than in either the control or schizotypal personality disorder groups, which did not differ from each other. The three groups did not differ significantly in total thalamic volume in square millimeters or thalamic volume relative to brain volume. Shape analyses revealed that schizophrenic patients had significantly fewer pixels in the left anterior region, whereas patients with schizotypal personality disorder had significantly fewer pixels in the region of the right mediodorsal nucleus than did control subjects. CONCLUSIONS: Schizophrenic patients showed significant metabolism and shape differences from control subjects in selective subregions of the thalamus, whereas patients with schizotypal personality disorder showed only a difference in shape. Because the mediodorsal and anterior nuclei have different connections with limbic and prefrontal structures, the anterior thalamic shrinkage and mediodorsal metabolic and shape changes might relate to the different clinical pictures in schizotypal personality disorder and schizophrenia.

Positron emission tomography with deoxyglucose-F18 imaging of sleep.

Positron emission tomography with deoxyglucose-F18 was obtained during nighttime sleep in 36 normal volunteers, 12 studied in rapid eye movement sleep (REM period 2), 12 in nonREM sleep, and 12 while awake with eyes closed. Metabolic rate was higher throughout the cortex in REM than nonREM sleep, with differences most marked in the cingulate and frontal cortex, thalamus, and visual association areas. Whole-brain metabolic rates in the waking condition were intermediate between those in REM and nonREM sleep. Metabolism in the primary visual cortex and parts of the lateral temporal lobe was relatively constant in the REM/nonREM conditions. REM sleep did not differ from either the nonREM or waking conditions in hemispheric lateralization of metabolic activity. Compared with REM sleep, nonREM sleep was associated with significantly lower metabolic rates in the temporal and occipital regions, as well as the thalamus.

d,l-fenfluramine response in impulsive personality disorder assessed with [18F]fluorodeoxyglucose positron emission tomography.

Reduced serotonergic activity has been associated with impulsive aggression in personality disordered patients in metabolite and pharmacologic challenge studies. This study used positron emission tomography to explore whether reduced serotonergic function occurs in critical brain regions such as orbital frontal and cingulate cortex that, may play a role in modulating aggression. Six impulsive-aggressive patients and five healthy volunteers were evaluated for changes in regional glucose metabolism after administration of the serotonergic releasing agent d,l-fenfluramine (60 mg, p.o.) or placebo. Volunteers demonstrated increases in orbital frontal and adjacent ventral medial frontal cortex, cingulate, and inferior parietal cortex, whereas impulsive-aggressive patients showed no significant increases in glucose metabolism after fenfluramine in any region. Compared with volunteers, patients showed significantly blunted metabolic responses in orbital frontal, adjacent ventral medial and cingulate cortex, but not in inferior parietal lobe. These results are consistent with reduced serotonergic modulation of orbital frontal, ventral medial frontal, and cingulate cortex in patients with impulsive-aggressive personality disorders.

Sensorimotor gating deficits and hypofrontality in schizophrenia.

Patients with schizophrenia exhibit (a) deficient sensorimotor gating as indexed by impaired prepulse inhibition (PPI) of the startle eyeblink reflex suggesting abnormal automatic information processing and (b) abnormal attentional modulation of PPI suggesting impaired controlled information processing. Here we test the hypothesis of deficient attentional modulation of PPI in schizophrenia as a defect in the interrelationship between frontal lobe functions of planning and executive action and posterior function of processing of sensory stimulation using positron emission tomography (PET). Consistent with the literature, our findings indicate that unmedicated schizophrenia patients exhibit lower frontal/occipital ratios (termed "hypofrontality") compared with healthy controls (n=15 in each group) during a standard tone-length-judgment (attention-to-prepulse) task. Moreover, better attentional modulation of PPI was associated with higher frontal/occipital ratios in the control, but not the patient group. These findings extend animal models to humans by demonstrating the importance of frontal and occipital lobe coordination in the modulation of PPI.

Functional brain imaging and aging in schizophrenia.

Patients with schizophrenia, even early in the course of illness, show some similarities in their brain-imaging findings to those in older normal controls: for example, ventricular enlargement and diminished functional activity in the frontal cortex. These findings suggest a possible similarity between the normal aging process and schizophrenia, or the possible existence in some schizophrenic patients of progressive processes that prematurely affect the brain in ways analogous to normal aging. In contrast to other brain regions, the basal ganglia in schizophrenia may show an atypical pattern of volumetric and metabolic change over time, possibly because of the effects of neuroleptic treatment. However, age and illness duration are highly correlated in our samples. Interpretation of imaging results is limited by the lack of studies in an adequate number of either first-break or older schizophrenic patients and the dearth of studies with longitudinal designs.

Shape and size of the corpus callosum in schizophrenia and schizotypal personality disorder.

The size and shape of the corpus callosum were assessed on sagittal section magnetic resonance images in 27 patients with schizophrenia, 13 patients with schizotypal personality disorder (SPD), and 30 healthy volunteers. High-resolution 1.2mm axial SPGR images were acquired and resectioned so that the sagittal plane passed through the anterior and posterior commissures and was parallel to the interhemispheric fissure. The corpus callosum and the whole brain were traced on midsagittal section slices of each brain, and the callosum was divided into 30 anteroposterior sectors. Pixel-by-pixel chi-square and thin-plate spline analyses were used to assess between-group shape differences. Size of the corpus callosum was smaller anteriorly in the genu of the corpus callosum and posteriorly in the splenium in schizophrenic patients than in normal controls. The genu of the corpus callosum was larger in SPD patients than in schizophrenic patients or normal controls. The posterior corpus callosum was largest in normal controls, smaller in SPD patients, and smallest in schizophrenic patients. Shape analysis was consistent with these size comparisons, and suggested a downward bowing of the corpus callosum in schizophrenic and SPD patients. SPD patients also had a region of the callosum just posterior to the genu that was narrower than in the other two groups. The decreases in corpus callosal size in schizophrenia varied directly with length of illness, perhaps indicative of a progressive process. The patient-control differences in callosal size and shape are consistent with a hypothesis of decreased connectivity between the left and the right hemispheres in schizophrenia and SPD.

Hypofrontality in unmedicated schizophrenia patients studied with PET during performance of a serial verbal learning task.

Previous research indicates that verbal learning and memory deficits are among the most severe cognitive deficits observed in schizophrenia. However, the concomitant patterns of regional brain function associated with these deficits in schizophrenia are not well understood. The present study examined verbal-memory performance and simultaneous relative glucose metabolic rates (rGMR) with FDG PET in 20 unmedicated schizophrenia patients who met stringent memory-performance criteria and 32 age- and sex-matched normal volunteers. On a modified version of the California Verbal Learning Test, patients recalled fewer correct words using a semantic-clustering strategy and exhibited more intrusions compared with normal subjects. However, patients had higher serial-ordering strategy scores, indicating their use of a less efficient organizational strategy. Among patients, greater use of the serial-ordering strategy was associated with decreased rGMR in frontal cortex and increased rGMR in temporal cortex. Patients had lower rGMR primarily in frontal and temporal cortex, but not parietal and occipital lobe regions. Patients also exhibited hypofrontality (lower ratio of frontal to occipital rGMR) compared with normal subjects. Among the patients, more severe hypofrontality was associated with increased perseveration errors.

Temporal lobe volume determined by magnetic resonance imaging in schizotypal personality disorder and schizophrenia.

The volumes of the whole temporal lobe, the superior temporal gyrus and the corpus callosum were measured on magnetic resonance images from 13 patients with schizotypal personality disorder (SPD), 27 patients with schizophrenia, and 31 age- and sex-matched controls. Temporal lobe structures were traced on consecutive 1.2mm thick SPGR images. Both patient groups had smaller temporal lobes than normal volunteers, a difference that was more marked for the area outside the superior temporal gyrus than for the STG. Correcting for brain volume diminished differences between normal subjects and schizophrenia patients, but the differences between normal subjects and SPD patients remained. Normal volunteers and SPD patients showed significant correlations between the sagittal section area of the posterior portion of the corpus callosum, which carries temporal interhemispheric connections, and the white matter volume of the temporal lobe. While the sample size is modest, taken together, these results suggest that the psychopathological symptoms of SPD may be related to temporal gray matter loss with relatively intact white matter connectivity, while the cognitive and psychotic symptoms of schizophrenia may be related to temporal gray loss combined with disruption of normal patterns of white matter development.

MRI white matter diffusion anisotropy and PET metabolic rate in schizophrenia.

A disturbance in the frontal-striatal-thalamic circuitry has been proposed for schizophrenia, but this concept has been based primarily on indirect evidence from psychopharmacology and analogies with animal research. Diffusion tensor imaging, a new MRI technique that permits direct assessment of the large axon masses stretching from the prefrontal cortex to the striatum, was used to study white matter axon bundles. Diffusion tensor images, high-resolution structural MRI and positron emission tomography scans with 18-fluorodexoyglucose were obtained on five patients with schizophrenia and six age- and sex-matched normal controls. Significantly lower diffusion anisotropy in the white matter of the prefrontal cortex in schizophrenic patients than in normal controls was observed in statistical probability maps. Co-registered PET scans revealed significantly lower correlation coefficients between metabolic rates in the prefrontal cortex and striatum in patients than in controls. These twin findings provide convergent evidence for diminished fronto-striatal connectivity in schizophrenia.

Positron emission tomography studies of abnormal glucose metabolism in schizophrenia.

Schizophrenia, a devastating disease characterized by a combination of various types of disturbed behaviors, thoughts, and feelings, may likewise be heterogeneous in etiology. Recent advances in neuroscience and psychopharmacology have suggested a wide array of competing mechanisms that may be involved in schizophrenia, including but not limited to deficits in one or more neurotransmitters and second messenger systems (e.g., dopamine, serotonin, gamma-aminobutyric acid, glutamate, and noradrenaline), neurodevelopmental defects in brain circuitry, and viral infection. Psychiatric genetic studies indicate that schizophrenia is a disorder with multifactorial inheritance. Since cerebral metabolic activity reflects regional brain work for all neurotransmitter systems, imaging metabolism directly with fluorodeoxyglucose and indirectly with blood flow and hemoglobin oxygen saturation can provide information about the functional neuroanatomy of a deficit in individual patients and allow patients to be grouped into more homogeneous subgroups for intensive study. This review summarizes metabolic imaging studies in schizophrenia over the past decade.