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1.  fMRI Assessment of Thalamocortical Connectivity during Attentional Performance 
Magnetic resonance imaging  2013;31(7):1112-1118.
Functional magnetic resonance imaging (fMRI) studies have shown dysfunction in key areas associated with the thalamocortical circuit in patients with schizophrenia. This study examined the functional connectivity involving the frontal-thalamic circuitry during a spatial focusing-of-attention task in 18 unmedicated patients with schizophrenia and 38 healthy controls. Functional connectivity was analyzed by assigning seed regions (in the thalamic nuclei (mediodorsal nucleus (MDN), pulvinar, anterior nucleus (AN)), the dorsolateral prefrontal cortex (Brodmann areas 9 and 46), and the caudate), and correlating their respective activity with that in the non-seed regions voxel-wise. Functional connectivity analysis demonstrated that functional connectivity was significantly impaired in patients e.g., between the right pulvinar and regions such as the prefrontal and temporal cortices and the cerebellum. On the other hand, enhanced functional connectivity was found in patients e.g., between the AN and regions such as the prefrontal and temporal cortices. In addition, the patients had significantly lower task performance and less (but non-significant) brain activation than those of controls. These results revealed disturbed functional integration in schizophrenia, and suggested that the functional connectivity abnormalities in the thalamocortical circuitry, especially the frontal-thalamic circuitry, may underlie the attention deficits in schizophrenia patients. Further, this study suggested that functional connectivity analysis might be more sensitive than brain activation analysis in detecting the functional abnormalities in schizophrenia.
PMCID: PMC3729917  PMID: 23727467
Thalamocortical circuitry; Functional connectivity; Spatial attention
2.  Larger putamen size in antipsychotic-naïve individuals with schizotypal personality disorder 
Schizophrenia research  2012;143(1):158-164.
To (a) compare the size of the dorsal and ventral striatum(caudate and putamen) in a large sample of antipsychotic-naïve individuals with schizotypal personality disorder (SPD) and healthy control participants; (b) examine symptom correlates of striatal size in SPD.
The left and right caudate and putamen were hand-traced on structural MRI at five dorsal to ventral slice levels in 76 SPD and 148 healthy control participants. A Group × Region (caudate, putamen) × Slice (1–5: ventral, 2, 3, 4, dorsal) × Hemisphere (left, right) mixed-model MANOVA was conducted on size relative to whole brain.
Primary results showed that compared with the controls, the SPD group showed (a) larger bilateral putamen size overall and this enlargement was more pronounced at the most ventral and dorsal levels; in contrast, there were no between-group differences in caudate volume; (b) larger bilateral size of the striatum ventrally, averaged across the caudate and putamen. Among the SPD group, larger striatal size ventrally, particularly in the left hemisphere was associated with less severe paranoid symptoms.
Striatal size is abnormal in SPD and resembles that of patients with schizophrenia who respond well to antipsychotic treatment. The results suggest that striatal size may be an important endophenotype to consider when developing new pharmacological treatments and when studying factors mitigating psychosis.
PMCID: PMC3634353  PMID: 23187070
Schizotypal personality disorder; Putamen; Caudate; Striatum; Schizophrenia; MRI; Striatal size
3.  Anterior limb of the internal capsule in schizotypal personality disorder: Fiber-tract counting, volume, and anisotropy 
Schizophrenia research  2012;141(0):119-127.
Mounting evidence suggests that white matter abnormalities and altered subcortical–cortical connectivity may be central to the pathology of schizophrenia (SZ). The anterior limb of the internal capsule (ALIC) is an important thalamo-frontal white-matter tract shown to have volume reductions in SZ and to a lesser degree in schizotypal personality disorder (SPD). While fractional anisotropy (FA) and connectivity abnormalities in the ALIC have been reported in SZ, they have not been examined in SPD. In the current study, magnetic resonance (MRI) and diffusion tensor imaging (DTI) were obtained in age- and sex-matched individuals with SPD (n=33) and healthy controls (HCs; n=38). The ALIC was traced bilaterally on five equally spaced dorsal-to-ventral axial slices from each participant’s MRI scan and co-registered to DTI for the calculation of FA. Tractography was used to examine tracts between the ALIC and two key Brodmann areas (BAs; BA10, BA45) within the dorsolateral prefrontal cortex (DLPFC). Compared with HCs, the SPD participants exhibited (a) smaller relative volume at the mid-ventral ALIC slice level but not the other levels; (b) normal FA within the ALIC; (c) fewer relative number of tracts between the most-dorsal ALIC levels and BA10 but not BA45 and (d) fewer dorsal ALIC–DLPFC tracts were associated with greater symptom severity in SPD. In contrast to prior SZ studies that report lower FA, individuals with SPD show sparing. Our findings are consistent with a pattern of milder thalamo-frontal dysconnectivity in SPD than schizophrenia.
PMCID: PMC3742803  PMID: 22995934
Schizotypal personality disorder; Diffusion tensor imaging; Tractography; Magnetic resonance imaging; Anisotropy; Internal capsule
4.  Potentiated amygdala response to repeated emotional pictures in borderline personality disorder 
Biological psychiatry  2012;72(6):448-456.
Borderline personality disorder (BPD) is characterized by an inability to regulate emotional responses. The amygdala is important in learning about the valence (goodness and badness) of stimuli and has been reported to function abnormally in BPD.
Event-related functional MRI (fMRI) was employed in three groups: unmedicated BPD (n=33) and schizotypal personality disorder (SPD;n=28) participants and healthy controls (n=32) during a task involving an intermixed series of unpleasant, neutral, and pleasant pictures each presented twice within their respective trial block/run. The amygdala was hand-traced on each participant’s structural-MRI scan which was co-registered to their BOLD-scan. Amygdala responses were examined with a mixed-model MANOVA with repeated measures.
Compared with both control groups, BPD patients showed greater amygdala activation, particularly to the repeated emotional but not neutral pictures and a prolonged return to baseline for the overall BOLD response averaged across all pictures. Despite amygdala overactivation, BPD patients showed a blunted response on the self-report ratings of emotional but not neutral pictures. Fewer dissociative symptoms in both patient groups were associated with greater amygdala activation to repeated unpleasant pictures.
The increased amygdala response to the repeated emotional pictures observed in BPD was not observed in SPD patients suggesting diagnostic specificity. This BPD-related abnormality is consistent with the well-documented clinical feature of high sensitivity to emotional stimuli with unusually strong and long-lasting reactions. The finding of a mismatch between physiological and self-report measures of emotion reactivity in BPD patients suggests they may benefit from treatments which help them recognize emotions.
PMCID: PMC3415575  PMID: 22560044
borderline personality disorder; schizotypal personality disorder; amygdala; emotion; fMRI; arousal; valence
5.  Brodmann Area Analysis of White Matter Anisotropy and Age in Schizophrenia 
Schizophrenia research  2011;130(1-3):57-67.
Diffusion tensor and structural MRI images were acquired on ninety-six patients with schizophrenia (69 men and 27 women between the ages of 18 and 79 (mean = 39.83, SD = 15.16 DSM-IV diagnosis of schizophrenia according to the Comprehensive Assessment of Symptoms and History). The patients reported a mean age of onset of 23 years (range = 13–38, SD = 6). Patients were divided into an acute subgroup (duration ≤ 3 years, n = 25), and a chronic subgroup (duration > 3 years, n = 64). Ninety-three mentally normal comparison subjects were recruited; 55 men and 38 women between the ages of 18 and 82 (mean = 35.77, SD = 18.12). The MRI images were segmented by Brodmann area, and the fractional anisotropy (FA) for the white matter within each Brodmann area was calculated. The FA in white matter was decreased in patients with schizophrenia broadly across the entire brain, but to a greater extent in white matter underneath frontal, temporal and cingulate cortical areas. Both normals and patients with schizophrenia showed a decrease in anisotropy with age but patients with schizophrenia showed a significantly greater rate of decrease in FA in Brodmann area 10 bilaterally, 11 in the left hemisphere and 34 in the right hemisphere. When the effect of age was removed, patients ill more than three years showed lower anisotropy in frontal motor and cingulate white matter in comparison to acute patients ill three years or less, consistent with an ongoing progression of the illness.
PMCID: PMC3139821  PMID: 21600737
Schizophrenia; White Matter; Diffusion Tensor Imaging; Anisotropy; Brodmann Areas; Age
6.  Anterior and Posterior Cingulate Cortex Volume in Healthy Adults: Effects of Aging and Gender Differences 
Brain research  2011;1401:18-29.
The cingulate cortex frequently shows gray matter loss with age as well as gender differences in structure and function, but little is known about whether individual cingulate Brodmann areas show gender-specific patterns of age-related volume decline. This study examined age-related changes, gender differences, and the interaction of age and gender in the relative volume of cingulate gray matter in areas 25, 24, 31, 23, and 29, over seven decades of adulthood. Participants included healthy, age-matched men and women, aged 20–87 (n = 70). Main findings were: (1) The whole cingulate showed significant age-related volume declines (averaging 5.54% decline between decades, 20s–80s). Each of the five cingulate areas also showed a significant decline with age, and individual areas showed different patterns of decline across the decades: Smaller volume with age was most evident in area 31, followed by 25 and 24. (2) Women had relatively larger cingulate gray matter volume than men overall and in area 24. (3) Men and women showed different patterns of age-related volume decline in area 31, at midlife and late in life. By delineating normal gender differences and age-related morphometric changes in the cingulate cortex over seven decades of adulthood, this study improves the baseline for comparison with structural irregularities in the cingulate cortex associated with psychopathology. The Brodmann area-based approach also facilitates comparisons across studies that aim to draw inferences between age- and gender-related structural differences in the cingulate gyrus and corresponding differences in cingulate function.
PMCID: PMC3134959  PMID: 21669408
Cingulate cortex; aging; gender differences; MRI; gray matter; morphometry
7.  18F-Fallypride binding potential in patients with schizophrenia compared to healthy controls 
Schizophrenia Research  2010;122(1-3):43-52.
Molecular imaging of dopaminergic parameters has contributed to the dopamine hypothesis of schizophrenia, expanding our understanding of pathophysiology, clinical phenomenology and treatment. Our aim in this study was to compare 18F-fallypride binding potential BPND in a group of patients with schizophrenia-spectrum illness vs. controls, with a particular focus on the cortex and thalamus.
We acquired 18F-fallypride positron emission tomography images on 33 patients with schizophrenia spectrum disorder (28 with schizophrenia; 5 with schizoaffective disorder) and 18 normal controls. Twenty-four patients were absolutely neuroleptic naïve and nine were previously medicated, although only four had a lifetime neuroleptic exposure of greater than two weeks. Parametric images of 18F-fallypride BPND were calculated to compare binding across subjects.
Decreased BPND was observed in the medial dorsal nucleus of the thalamus, prefrontal cortex, lateral temporal lobe and primary auditory cortex. These findings were most marked in subjects who had never previously received medication.
The regions with decreased BPND tend to match brain regions previously reported to show alterations in metabolic activity and blood flow and areas associated with the symptoms of schizophrenia.
PMCID: PMC3278159  PMID: 20655709
Schizophrenia; Dopamine; Molecular imaging; Positron emission tomography; Thalamus; Cortex
8.  A Pilot Study of Quantitative MRI Measurements of Ventricular Volume and Cortical Atrophy for the Differential Diagnosis of Normal Pressure Hydrocephalus 
Current radiologic diagnosis of normal pressure hydrocephalus (NPH) requires a subjective judgment of whether lateral ventricular enlargement is disproportionate to cerebral atrophy based on visual inspection of brain images. We investigated whether quantitative measurements of lateral ventricular volume and total cortical thickness (a correlate of cerebral atrophy) could be used to more objectively distinguish NPH from normal controls (NC), Alzheimer's (AD), and Parkinson's disease (PD). Volumetric MRIs were obtained prospectively from patients with NPH (n = 5), PD (n = 5), and NC (5). Additional NC (n = 5) and AD patients (n = 10) from the ADNI cohort were examined. Although mean ventricular volume was significantly greater in the NPH group than all others, the range of values overlapped those of the AD group. Individuals with NPH could be better distinguished when ventricular volume and total cortical thickness were considered in combination. This pilot study suggests that volumetric MRI measurements hold promise for improving NPH differential diagnosis.
PMCID: PMC3154385  PMID: 21860791
9.  Poor outcome in chronic schizophrenia is associated with progressive loss of volume of the putamen 
Schizophrenia research  2009;113(2-3):241-245.
We have previously demonstrated that putaminal but not caudate volumes are associated with poor outcome in patients with chronic schizophrenia. Present longitudinal study was designed to investigate progressive differences in striatal volumes among chronic schizophrenia patients with different outcomes and healthy subjects.
Structural MRI scans were acquired at baseline and at follow-up four years later to evaluate volumetric changes in 26 poor-outcome schizophrenia patients, 23 good-outcome patients and 16 healthy subjects.
Schizophrenia patients with different outcomes entered the study with similar volumes of the caudate nucleus and putamen. The rate of decline in volumes of the putamen was greater in patients with poor outcome than in the good-outcome group, so that their putaminal but not caudate volumes were significantly smaller at the time of follow-up. There were no differences in baseline and follow-up volumes of the putamen or in the rate of their progression among patients with schizophrenia and healthy comparison subjects. The caudate volumes were lower in schizophrenia patients than healthy subjects at baseline and follow-up, but showed no differential patterns of progression between the groups.
Volumes of the putamen may represent a longitudinal marker of treatment responsiveness and outcome in patients with chronic schizophrenia.
PMCID: PMC2763420  PMID: 19616411
Chronic schizophrenia; caudate nucleus; putamen; poor outcome; Kraepelinian; striatum
10.  Frontal-striatal-thalamic mediodorsal nucleus dysfunction in schizophrenia-spectrum patients during sensorimotor gating 
NeuroImage  2008;42(3):1164-1177.
Prepulse inhibition (PPI) refers to a reduction in the amplitude of the startle eye-blink reflex to a strong sensory stimulus, the pulse, when it is preceded shortly by a weak stimulus, the prepulse. PPI is a measure of sensorimotor gating which serves to prevent the interruption of early attentional processing and it is impaired in schizophrenia-spectrum patients. In healthy individuals, PPI is more robust when attending to than ignoring a prepulse. Animal and human work demonstrate frontal-striatal-thalamic (FST) circuitry modulates PPI. This study used functional magnetic resonance imaging (fMRI) to investigate FST-circuitry during an attention-to-prepulse paradigm in 26 unmedicated schizophrenia-spectrum patients (13 schizotypal personality disorder (SPD), 13 schizophrenia) and 13 healthy controls. During 3T-fMRI acquisition and separately measured psychophysiological assessment of PPI, participants heard an intermixed series of high- and low-pitched tones serving as prepulses to an acoustic-startle stimulus. Event-related BOLD-response amplitude curves in FST regions traced on co-registered anatomical MRI were examined. Controls showed greater activation during attended than ignored PPI conditions in all FST regions--dorsolateral prefrontal cortex (Brodmann areas 46,9), striatum (caudate, putamen), and the thalamic mediodorsal nucleus (MDN). In contrast, schizophrenia patients failed to show differential BOLD responses in FST-circuitry during attended and ignored prepulses, whereas SPD patients showed greater-than-normal activation during ignored prepulses. Among the three diagnostic groups, lower left caudate BOLD activation during the attended PPI condition was associated with more deficient sensorimotor gating as measured by PPI. Schizophrenia-spectrum patients exhibit inefficient utilization of FST-circuitry during attentional modulation of PPI. Schizophrenia patients have reduced recruitment of FST-circuitry during task-relevant stimuli, whereas SPD patients allocate excessive resources during task-irrelevant stimuli. Dysfunctional FST activation, particularly in the caudate may underlie PPI abnormalities in schizophrenia-spectrum patients.
PMCID: PMC2548278  PMID: 18588988
dorsolateral prefrontal cortex; caudate nucleus; putamen; thalamus; mediodorsal nucleus; fMRI; schizophrenia; schizotypal personality disorder; startle; prepulse inhibition; attention; sensorimotor gating
11.  The Effect of Doxapram on Brain Imaging In Patients with Panic Disorder 
Administration of doxapram hydrochloride, a respiratory stimulant, is experienced by panic disorder patients to be similar to panic attacks but has reduced emotional effect in normal volunteers thus providing a laboratory model of panic for functional imaging. Six panic patients and seven normal control subjects underwent positron emission tomography with 18F-deoxyglucose imaging after a single-blinded administration of either doxapram or a placebo saline solution. Saline and doxapram were administered on separate days in counterbalanced order. Patients showed a greater heart rate increase on doxapram from saline than controls, indicating differential response. On the saline placebo day, patients had greater prefrontal relative activity than controls. In response to doxapram, patients tended to decrease prefrontal activity more than controls, and increased cingulate gyrus and amygdala activity more than controls. This suggests that panic disorder patients activate frontal inhibitory centers less than controls which may lower the threshold for panic.
PMCID: PMC2695988  PMID: 17560768
doxapram; PET; panic; prefrontal cortex; amygdala; neuroimaging
12.  Longitudinal Assessment of Gray and White Matter in Chronic Schizophrenia: A Combined Diffusion-Tensor and Structural Magnetic Resonance Imaging Study 
Previous studies have reported continued focal gray matter loss after the clinical onset of schizophrenia. Longitudinal assessments in chronic illness, of white matter in particular, have been less conclusive.
We used diffusion-tensor and structural magnetic resonance imaging in 16 healthy subjects and 49 chronic schizophrenia patients, subdivided into good-outcome (n=23) and poor-outcome (n=26) groups, scanned twice 4 years apart. Fractional anisotropy, gray matter and white matter volumes were parcellated into the Brodmann’s areas and entered into multiway ANCOVAs.
At baseline, schizophrenia patients had 1) lower anisotropy in frontoparietal white matter, 2) larger posterior frontal white matter volumes, and 3) smaller frontal, temporal, and parietal gray matter volumes. On follow-up, healthy subjects showed a more pronounced 1) decline in anisotropy, 2) expansion of regional white matter volumes, and 3) reduction in regional gray matter volumes than schizophrenia patients. Good-outcome patients showed a more pronounced decline in white matter anisotropy and a less pronounced increase in white matter volumes than poor-outcome patients. Poor-outcome patients displayed a greater gray matter loss throughout the brain than good-outcome patients.
In the chronic phase of the illness, longitudinal changes in both gray and white matter are in the direction of an effacement of between-group differences among schizophrenia patients and healthy subjects. Similarly, preexisting white matter differences between good-outcome and poor-outcome patients diminish over time. In contrast, gray matter volumes in poor-outcome patients continue to decline more rapidly than in patients with good outcome. These patterns are consistent with earlier onset of aging-associated changes in schizophrenia.
PMCID: PMC2700015  PMID: 19547667
Kraepelinian schizophrenia; poor outcome; anisotropy; white matter; illness progression.
13.  Diffusion tensor imaging of frontal lobe white matter tracts in schizophrenia 
We acquired diffusion tensor and structural MRI images on 103 patients with schizophrenia and 41 age-matched normal controls. The vector data was used to trace tracts from a region of interest in the anterior limb of the internal capsule to the prefrontal cortex. Patients with schizophrenia had tract paths that were significantly shorter in length from the center of internal capsule to prefrontal white matter. These tracts, the anterior thalamic radiations, are important in frontal-striatal-thalamic pathways. These results are consistent with findings of smaller size of the anterior limb of the internal capsule in patients with schizophrenia, diffusion tensor anisotropy decreases in frontal white matter in schizophrenia and hypothesized disruption of the frontal-striatal-thalamic pathway system.
PMCID: PMC1687182  PMID: 17132158

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