Paul G. Nestor

DTI and MTR abnormalities in schizophrenia: Analysis of white matter integrity

Diffusion tensor imaging (DTI) studies in schizophrenia demonstrate lower anisotropic diffusion within white matter due either to loss of coherence of white matter fiber tracts, to changes in the number and/or density of interconnecting fiber tracts, or to changes in myelination, although methodology as well as localization of such changes differ between studies. The aim of this study is to localize and to specify further DTI abnormalities in schizophrenia by combining DTI with magnetization transfer imaging (MTI), a technique sensitive to myelin and axonal alterations in order to increase specificity of DTI findings. 21 chronic schizophrenics and 26 controls were scanned using Line-Scan-Diffusion-Imaging and T1-weighted techniques with and without a saturation pulse (MT). Diffusion information was used to normalize co-registered maps of fractional anisotropy (FA) and magnetization transfer ratio (MTR) to a study-specific template, using the multi-channel daemon algorithm, designed specifically to deal with multidirectional tensor information. Diffusion anisotropy was decreased in schizophrenia in the following brain regions: the fornix, the corpus callosum, bilaterally in the cingulum bundle, bilaterally in the superior occipito-frontal fasciculus, bilaterally in the internal capsule, in the right inferior occipito-frontal fasciculus and the left arcuate fasciculus. MTR maps demonstrated changes in the corpus callosum, fornix, right internal capsule, and the superior occipito-frontal fasciculus bilaterally; however, no changes were noted in the anterior cingulum bundle, the left internal capsule, the arcuate fasciculus, or inferior occipito-frontal fasciculus. In addition, the right posterior cingulum bundle showed MTR but not FA changes in schizophrenia. These findings suggest that, while some of the diffusion abnormalities in schizophrenia are likely due to abnormal coherence, or organization of the fiber tracts, some of these abnormalities may, in fact, be attributed to or coincide with myelin/axonal disruption.

Cingulate fasciculus integrity disruption in schizophrenia: a magnetic resonance diffusion tensor imaging study

Evidence suggests that a disruption in limbic system network integrity and, in particular, the cingulate gyrus (CG), may play a role in the pathophysiology of schizophrenia; however, the cingulum bundle (CB), the white matter tract furnishing both input and output to CG, and the most prominent white matter fiber tract in the limbic system, has not been evaluated in schizophrenia using the new technology of diffusion tensor imaging (DTI). We used line scan DTI to evaluate diffusion in the CB in 16 male schizophrenia patients and 18 male control subjects, group-matched for age, parental socioeconomic status, and handedness. We acquired 4-mm-thick coronal slices through the entire brain. Maps of fractional anisotropy (FA) were generated to quantify diffusion within the left and right CB on eight slices that included the central portion of the CB. Results showed group differences, bilaterally, in area and mean FA for CB, where patients showed smaller area and less anisotropy than controls. For patients, decreased left CB correlated significantly with attention and working memory measures as assessed by the Wisconsin Card Sorting Test. These data provide strong evidence for CB disruptions in schizophrenia, which may be related to disease-related attention and working memory abnormalities.

Left Auditory Cortex Gamma Synchronization and Auditory Hallucination Symptoms in Schizophrenia

BackgroundOscillatory electroencephalogram (EEG) abnormalities may reflect neural circuit dysfunction in neuropsychiatric disorders. Previously we have found positive correlations between the phase synchronization of beta and gamma oscillations and hallucination symptoms in schizophrenia patients. These findings suggest that the propensity for hallucinations is associated with an increased tendency for neural circuits in sensory cortex to enter states of oscillatory synchrony. Here we tested this hypothesis by examining whether the 40 Hz auditory steady-state response (ASSR) generated in the left primary auditory cortex is positively correlated with auditory hallucination symptoms in schizophrenia. We also examined whether the 40 Hz ASSR deficit in schizophrenia was associated with cross-frequency interactions.Sixteen healthy control subjects (HC) and 18 chronic schizophrenia patients (SZ) listened to 40 Hz binaural click trains. The EEG was recorded from 60 electrodes and average-referenced offline. A 5-dipole model was fit from the HC grand average ASSR, with 2 pairs of superior temporal dipoles and a deep midline dipole. Time-frequency decomposition was performed on the scalp EEG and source data.ResultsPhase locking factor (PLF) and evoked power were reduced in SZ at fronto-central electrodes, replicating prior findings. PLF was reduced in SZ for non-homologous right and left hemisphere sources. Left hemisphere source PLF in SZ was positively correlated with auditory hallucination symptoms, and was modulated by delta phase. Furthermore, the correlations between source evoked power and PLF found in HC was reduced in SZ for the LH sources.ConclusionThese findings suggest that differential neural circuit abnormalities may be present in the left and right auditory cortices in schizophrenia. In addition, they provide further support for the hypothesis that hallucinations are related to cortical hyperexcitability, which is manifested by an increased propensity for high-frequency synchronization in modality-specific cortical areas.

Caudate, putamen, and globus pallidus volume in schizophrenia: a quantitative MRI study.

Basal ganglia structures have been reported to be abnormal in schizophrenia. However, while component structures of the basal ganglia are functionally differentiated, there have been no evaluations of their separate magnetic resonance imaging (MRI) volumes with small voxel (1.5 mm3) spoiled gradient-recalled acquisition in steady state techniques and multi-plane assessments. We examined MRI scans from 15 male, right-handed, neuroleptic-medicated schizophrenic patients and 15 age-, handedness-, and gender-matched normal volunteers. Compared with normal subjects, schizophrenic patients showed enlarged volumes: 14.2% for total basal ganglia, 27.4% for globus pallidus, 15.9% for putamen, and 9.5% for caudate. Increased volumes, especially of the caudate, were associated with poorer neuropsychological test performance on finger tapping and Hebbs Recurring Digits. These findings indicate abnormalities throughout all basal ganglia structures in at least a subgroup of schizophrenic patients.

The auditory N2 component in schizophrenia: Relationship to MRI temporal lobe gray matter and to other ERP abnormalities

The N2 component of the auditory event-related potential (ERP) indexes cognitive processes involved in the categorization of deviant stimuli. Although N2 amplitude and latency abnormalities have been reported in schizophrenia, their relationship to MRI structural changes, clinical status, and P3 abnormalities has not been defined. We therefore studied the auditory N2 and P3 components elicited by an oddball paradigm in 15 right-handed male subjects with schizophrenia and 14 control subjects who had quantitative MRI measures of temporal lobe gray-matter structures. To provide a methodological comparison, we measured the auditory N2 from both the target ERP (N2t) and the target-minus-frequent ERP difference (N2d) waveforms. Both N2t and N2d amplitude were bilaterally reduced in schizophrenics, with N2d showing a more pronounced reduction. Within the schizophrenic group, N2 amplitude reduction was associated with reduction in gray-matter volume of the left superior temporal gyrus (STG) and of medial temporal lobe structures bilaterally, and clinically, with greater chronicity. P3 amplitude, in contrast, correlated only with left posterior STG volume, and was more prominently associated with delusions and thought disorder. These findings suggest that the N2 and P3 components, though occurring sequentially in the ERP, tap separable anatomic and behavioral abnormalities in schizophrenia.

Attention and driving skills in aging and Alzheimer's disease

The number of older drivers with dementia is rising with the aging of the adult population. A public health issue is growing because of concerns about the motor vehicle accident risk posed by drivers with dementia of the Alzheimers type (DAT) and other progressive, degenerative dementias. However, little is known about the specific perceptual/cognitive deficits contributing to impaired driving in DAT. The present paper proposes, on both theoretical and empirical grounds, that attentional skills in relation to driving should be examined in older adults with and without DAT. Such investigations should focus on normal older adults and those in the mild, early stages of dementia because the latter are the most likely among the dementia population to be still driving. Evidence is presented indicating (1) that motor vehicle accident rates are related to performance on information-processing measures of different components of attention; (2) that this relationship is greatest for measures of the switching of selective attention and less for that of divided and sustained attention (vigilance); and (3) that many of these same attentional functions, and particularly the switching of visual selective attention, are impaired in the early stages of DAT and thus may contribute to increased accident risk. Further studies of cognitive and driving performance in older drivers are necessary to establish that the attentional impairments found in mild DAT contribute to increased accident risk. Implications of these findings for driver assessment, education, and training are discussed.

Fornix Integrity and Hippocampal Volume in Male Schizophrenic Patients

BACKGROUND The hippocampus has been shown to be abnormal in schizophrenia. The fornix is one of the main fiber tracts connecting the hippocampus with other brain regions. Few studies have evaluated the fornix in schizophrenia, however. A focus on fornix abnormalities and their association with hippocampal abnormalities might figure importantly in our understanding of the pathophysiology of schizophrenia. METHODS Line-scan diffusion tensor imaging (DTI) was used to evaluate diffusion in the fornix in 24 male patients with chronic schizophrenia and 31 male control subjects. Maps of fractional anisotropy (FA) and mean diffusivity (D(m)), which are indices sensitive to white-matter integrity, were generated to quantify diffusion within the fornix. We used high spatial resolution magnetic resonance imaging (MRI) to measure hippocampal volume. RESULTS FA and cross-sectional area of the fornix were significantly reduced in patients compared with control subjects. D(m) was significantly increased, whereas hippocampal volume was bilaterally reduced in patients. Reduced hippocampal volume was correlated with increased mean D(m) and reduced cross-sectional area of the fornix for patients. Patients also showed a significant correlation between reduced scores on neuropsychologic measures of declarative-episodic memory and reduced hippocampal volumes. CONCLUSIONS These findings demonstrate a disruption in fornix integrity in patients with schizophrenia.

Neuropsychological Correlates of Diffusion Tensor Imaging in Schizophrenia

Patients with schizophrenia (n = 41) and healthy comparison participants (n = 46) completed neuropsychological measures of intelligence, memory, and executive function. A subset of each group also completed magnetic resonance diffusion tensor imaging (DTI) studies (fractional anisotropy and cross-sectional area) of the uncinate fasciculus (UF) and cingulate bundle (CB). Patients with schizophrenia showed reduced levels of functioning across all neuropsychological measures. In addition, selective neuropsychological-DTI relationships emerged. Among patients but not controls, lower levels of declarative-episodic verbal memory correlated with reduced left UF, whereas executive function errors related to performance monitoring correlated with reduced left CB. The data suggested abnormal DTI patterns linking declarative-episodic verbal memory deficits to the left UF and executive function deficits to the left CB among patients with schizophrenia.

ERP assessment of visual and auditory language processing in schizophrenia

Language disturbance in schizophrenia has been recently attributed to disturbed priming mechanisms. In the present study, event-related potentials (ERPs), were recorded to final words in sentences presented to 13 chronic patients with schizophrenia and 12 normal controls. Half of the final words fit a sentence context and another half did not. The N400 (the ERP sensitive to language) latency was prolonged, and its amplitude was more negative to both correct and incorrect sentence endings in the group with schizophrenia relative to the group of normal controls. The early ERP components, N100 and P200, were similar in both groups. These results suggest that language abnormalities in schizophrenia are related to a dysfunction in the language system and not to a general cognitive dysfunction, and may be related to poor use of context in patients with schizophrenia.

ATTENTIONAL NETWORKS AND CINGULUM BUNDLE IN CHRONIC SCHIZOPHRENIA

Thirty patients with chronic schizophrenia and 30 age-matched controls performed the Attention Network Test (ANT). A subset of the patient group (n=18) also had available magnetic resonance diffusion tensor imaging (DTI) measures of the cingulum bundle (CB) fractional anisotropy and volume. The patients showed a significantly different pattern of ANT performance, characterized primarily by decreased alerting efficiency. In addition, left CB fractional anisotropy correlated significantly with orienting of attention. Smaller right CB volume also correlated with reduced alertness, but not when covarying for medication and illness duration.