Peter Stoeter

Ultrastructural Hippocampal and White Matter Alterations in Mild Cognitive Impairment: A Diffusion Tensor Imaging Study

Mild cognitive impairment (MCI) is considered to be a transitional stage between normal aging and dementia. In Alzheimer’s disease (AD), white matter structural pathology is due to Wallerian degeneration and central angiopathy. However, in MCI patients, the presence and extent of white matter alterations as a possible correlate of impaired memory function and as predictor of subsequent progression to AD is not clarified yet. Diffusion tensor imaging (DTI) reveals the ultrastructural integrity of cerebral white matter tracts. Therefore, it could detect pathological processes that modify tissue integrity in patients with MCI. In our prospective study, conventional and diffusion tensor MR scans were obtained from 14 patients with MCI, 19 patients with AD, and 10 healthy controls. Mean diffusivity (MD) and fractional anisotropy (FA) were measured in temporal, frontal, parietal and occipital white matter regions as well as in the corpus callosum (genu and splenium) and the hippocampus. MCI patients showed higher MD values in the left centrum semiovale (p = 0.013; right: p = 0.026), in the left temporal (p = 0.006), the right temporal (p = 0.014) and the left hippocampal (p = 0.002) region as compared to the control group. FA values of MCI patients and controls did not differ significantly in any region. Compared to controls, AD patients had increased MD values in the left centrum semiovale (p = 0.012), the left parietal (p = 0.001), the right parietal (p = 0.028), the left temporal (p = 0.018), the right temporal (p = 0.011) and the left hippocampal region (p = 0.002). Decreased FA values were measured in the left temporal area (p = 0.017) and in the left hippocampus (p = 0.031) in AD patients compared to controls. FA and MD values did not differ significantly between AD and MCI patients. Elevated MD values indicating brain tissue alterations in MCI patients were found in regions that are typically involved in early changes due to AD, particularly the left hippocampus. The sensitivity of distinguishing MCI patients from controls was 71.4% (with a specificity set at 80%). Therefore, the DTI technique validates the MCI concept, and diffusion tensor MR measurement can be a helpful tool to quantify MCI pathology in vivo.

Color-coded diffusion-tensor-imaging of posterior cingulate fiber tracts in mild cognitive impairment.

Different processes like microvascular dysfunction, free radical toxicity, beta-amyloid deposits, and Wallerian degeneration can cause functionally relevant disturbances of cerebral neuronal networks by myelin degeneration. Color-coded diffusion-tensor-imaging (ccDTI) allows the structural identification and quantification of myelinated fiber tracts. Particularly, posterior cingulate fiber tracts, which are regarded as important neuronal substrates of the network representing memory processing can be localized only imprecisely by conventional magnetic resonance imaging techniques. The posterior cingulate bundles were assessed by ccDTI in 17 patients with amnestic mild cognitive impairment (MCI), 25 patients with Alzheimers dementia (DAT), and 21 age-matched controls. Additionally, DTI values were correlated with memory performance in the delayed verbal recall test. Fractional anisotropy and mean diffusivity differed significantly between MCI and controls, as well as between DAT and controls. Performance in the delayed verbal recall test of the entire study group correlated significantly with posterior cingulate bundle anisotropy and diffusivity. Using ccDTI seems, hence, a favorable strategy to detect and quantify the structural integrity of posterior cingulate white matter in MCI. Alterations of DTI parameters substantiate the involvement of white matter pathology in the development of MCI. Moreover, ccDTI could serve as in vivo method to investigate age and disease-related myelin alterations as potential morphological substrates of cognitive dysfunction.

Functional implications of hippocampal volume and diffusivity in mild cognitive impairment

Hippocampal atrophy has been related to mild cognitive impairment (MCI) and early Alzheimer disease (AD), but the diagnostic significance of cross-sectionally determined hippocampal volumes is still ambiguous. Diffusion-Tensor-Imaging (DTI) in MCI patients revealed an association of microstructural changes in hippocampal areas with verbal memory decline. MRI volumetry and DTI were combined to investigate 18 MCI patients attending a memory clinic, and 18 carefully age- and gender-matched healthy controls. Neuropsychological testing, high resolution T1-weighted volume MRI scans, and DTI scans with regions-of-interest in hippocampal areas were applied. Left hippocampal volume was significantly lower (-11%, P = 0.02) in MCI patients than in control subjects. No significant differences were found for the right hippocampus (-4%). Mean diffusivity (MD) was significantly elevated in MCI patients vs. controls in left (+10%, P = 0.002) and right hippocampal areas (+13%, P = 0.02). Hippocampal volume and MD values were not significantly correlated. Combining left hippocampal volume and MD measures showed that lower left hippocampal volumes were associated with poor verbal memory performance particularly when co-occurring with high MD values. No comparable associations could be found regarding the right hippocampal formation and with respect to non-verbal memory function. The results demonstrate that microstructural abnormalities as revealed by DTI are very sensitive early indicators of hippocampal dysfunction. The combination of macro- and microstructural parameters in hippocampal areas could be promising in early detection of neurodegenerative processes.

Occurence and Clinical Predictors of Spasticity After Ischemic Stroke

Background and Purpose— There is currently no consensus on (1) the percentage of patients who develop spasticity after ischemic stroke, (2) the relation between spasticity and initial clinical findings after acute stroke, and (3) the impact of spasticity on activities of daily living and health-related quality of life. Methods— In a prospective cohort study, 301 consecutive patients with clinical signs of central paresis due to a first-ever ischemic stroke were examined in the acute stage and 6 months later. At both times, the degree and pattern of paresis and muscle tone, the Barthel Index, and the EQ-5D score, a standardized instrument of health-related quality of life, were evaluated. Spasticity was assessed on the Modified Ashworth Scale and defined as Modified Ashworth Scale >1 in any of the examined joints. Results— Two hundred eleven patients (70.1%) were reassessed after 6 months. Of these, 42.6% (n=90) had developed spasticity. A more severe degree of spasticity (Modified Ashworth Scale ≥3) was observed in 15.6% of all patients. The prevalence of spasticity did not differ between upper and lower limbs, but in the upper limb muscles, higher degrees of spasticity (Modified Ashworth Scale ≥3) were more frequently (18.9%) observed than in the lower limbs (5.5%). Regression analysis used to test the differences between upper and lower limbs showed that patients with more severe paresis in the proximal and distal limb muscles had a higher risk for developing spasticity (P≤0.001). Spasticity of the upper and lower limb was more frequent in patients with hemihypesthesia than in patients without sensory deficits (P≤0.001). Patients with spasticity showed a lower Barthel Index and EQ-5D score compared with the group without spasticity. Conclusions— Spasticity was present in 42.6% of patients with initial central paresis. However, severe spasticity was relatively rare. Predictors for the development of spasticity were a severe degree of paresis and hemihypesthesia at stroke onset.

Disturbed structural connectivity is related to inattention and impulsivity in adult attention deficit hyperactivity disorder.

Inattention and impulsivity are the most prominent clinical features of attention deficit hyperactivity disorder (ADHD) in adulthood. Structural and functional neuroimaging studies of subjects with ADHD have demonstrated abnormalities in several brain areas, including fronto‐striatal and fronto‐cerebellar networks. Mostly, these studies were based on volumetric measurements and have been conducted in children. We investigated white matter (WM) integrity and correlation with measures of attention and impulsivity in adult patients with ADHD adopting diffusion tensor imaging (DTI). N = 37 (21 males) never‐medicated adult patients with ADHD combined subtype and N = 34 (16 males) healthy controls were investigated. ADHD diagnosis (DSM‐IV) was assessed with clinical interviews and rating scales, subjects also underwent a large neuropsychological test battery including tests of attention and impulsivity. DTI was acquired, and group differences of fractional anisotropy (FA) and mean diffusivity (MD) as well as correlation analyses with measures of attentional performance and impulsivity were calculated using voxel‐based analyses. In adult patients with ADHD, we found reduced FA as well as higher MD bilaterally in orbitomedial prefrontal WM and in the right anterior cingulate bundle, while elevated FA was present bilaterally in temporal WM structures. Measures of attention were correlated with DTI parameters in the right superior longitudinal fasciculus, whereas measures of impulsivity were correlated with FA in right orbitofrontal fibre tracts. This is the first DTI study demonstrating disturbed structural connectivity of the frontal‐striatal circuitry in adult patients with ADHD. Moreover, a direct correlation between WM integrity and measures of attention and impulsivity is shown.

Left-hemisphere dominance in early nociceptive processing in the human parasylvian cortex.

Pain perception comprises sensory and emotional dimensions. While the emotional experience is thought to be represented in the right hemisphere, we here report a left-hemisphere dominance for the early sensory component of pain perception using brain electrical source analysis of laser-evoked potentials. Ten right-handed subjects underwent several series of laser radiant heat stimuli to pairs of parallel lines on the dorsum of the left or right hand. Stimulus location and intensity were randomised independently. The sensory-discriminative aspects of pain were emphasised by asking the subjects to perform either a spatial or an intensity discrimination task and were contrasted with active distraction by mental arithmetics. Pain ratings obtained after each of the laser stimulus series revealed an analgesic effect of distraction (27%, P < 0.001). Four equivalent dipole sources were active in the latency range of 100-200 ms (bilateral operculoinsular cortex, midcingulate gyrus, postcentral gyrus). The sources in the operculoinsular cortex exhibited (a) the shortest peak latency (155 +/- 6 ms), (b) the most pronounced enhancement during spatial and intensity discrimination tasks compared to active distraction (43%, P < 0.001), and (c) a significantly stronger source activity in the left hemisphere independent of stimulation side (23%, P < 0.05). The distribution of these sources extended into the dorsal insula. The postcentral source had the longest peak latency (180 +/- 7 ms); its source strength was task-dependent (25%, P = 0.051) but exhibited no hemisphere dominance. The midcingulate source had an intermediate peak latency (169 +/- 7 ms). Its source strength was modulated by tasks, but this modulation was significant only in the latency range >200 ms (46%, P < 0.001). These findings suggest a dominant role of the left frontal operculum and adjacent dorsal insula in the early sensory-discriminative dimensions of pain processing. This region has been proposed to be the cortical projection target of nociceptive pathways from the spinal cord to the ventroposteroinferior and ventromedial (its posterior part: VMpo) thalamic nuclei.

Contribution of diffusion tensor imaging to delineation of gliomas and glioblastomas.

To determine if the diffusion tensor imaging (DTI) parameters fractional anisotropy (FA) and mean diffusivity (MD) can differentiate between accompanying edema and tumor cell infiltration of white matter (WM) beyond the tumor edge as defined from conventional MRI in low‐ and high‐grade gliomas.

Diagnostic utility of hippocampal size and mean diffusivity in amnestic MCI

Hippocampus atrophy is a frequent finding in mild cognitive impairment (MCI), whereas diffusion-tensor-imaging (DTI) has demonstrated its value to detect subtle brain tissue changes in several neuropsychiatric diseases including MCI. To compare the diagnostic accuracy of both methods, high resolution MRI scans for hippocampus volumetry, and co-registered DTI-scans for ROI-based mean diffusivity (MD) and fractional anisotropy (FA) were carried out in 18 patients with amnestic MCI (7 females, age 67.3+/-8.7 years, MMSE 25.2+/-2.2) and 18 controls (age 66.9+/-9.0 years, MMSE 28.7+/-1.0). Diagnostic properties of normalized hippocampus volume (HV) and DTI measures with regard to MCI status were estimated by receiver operating characteristics (ROC) analyses and logistic regression. Parameters of the left hippocampus showed superior predictive power when compared to the right. At a specificity set to 80%, left HV had low sensitivity (50%); left hippocampal MD values revealed superior sensitivity (89%), similar to left hippocampal FA (78%). The results demonstrate higher sensitivity of DTI-derived left hippocampal parameters than volume measures in detecting subtle hippocampal abnormalities related to MCI.

Covariations Among fMRI, Skin Conductance, and Behavioral Data During Processing of Concealed Information

Imaging techniques have been used to elucidate the neural correlates that underlie deception. The scientifically best understood paradigm for the detection of deception, however, the guilty knowledge test (GKT), was rarely used in imaging studies. By transferring a GKT‐paradigm to a functional magnetic resonance imaging (fMRI) study, while additionally quantifying reaction times and skin conductance responses (SCRs), this study aimed at identifying the neural correlates of the behavioral and electrodermal response pattern typically found in GKT examinations. Prior to MR scanning, subjects viewed two specific items (probes) and were instructed to hide their knowledge of these. Two other specific items were designated as targets and required a different behavioral response during the experiment and eight items served as irrelevant stimuli. Reaction times and SCR amplitudes differed significantly between all three item types. The neuroimaging data revealed that right inferior frontal and mid‐cingulate regions were more active for probe and target trials compared to irrelevants. Moreover, the differential activation in the right inferior frontal region was modulated by stimulus conflicts. These results were interpreted as an increased top‐down influence on the stimulus‐response‐mapping for concealed and task‐relevant items. Additionally, the influence of working memory and retrieval processes on this activation pattern is discussed. Using parametric analyses, reaction times and SCR amplitudes were found to be linearly related to activity in the cerebellum, the right inferior frontal cortex, and the supplementary motor area. This result provides a first link between behavioral measures, sympathetic arousal, and neural activation patterns during a GKT examination. Hum Brain Mapp 2007.

Multiple Somatotopic Representations of Heat and Mechanical Pain in the Operculo-Insular Cortex: A High-Resolution fMRI Study

Whereas studies of somatotopic representation of touch have been useful to distinguish multiple somatosensory areas within primary (SI) and secondary (SII) somatosensory cortex regions, no such analysis exists for the representation of pain across nociceptive modalities. Here we investigated somatotopy in the operculo-insular cortex with noxious heat and pinprick stimuli in 11 healthy subjects using high-resolution (2 × 2 × 4 mm) 3T functional magnetic resonance imaging (fMRI). Heat stimuli (delivered using a laser) and pinprick stimuli (delivered using a punctate probe) were directed to the dorsum of the right hand and foot in a balanced design. Locations of the peak fMRI responses were compared between stimulation sites (hand vs. foot) and modalities (heat vs. pinprick) within four bilateral regions of interest: anterior and posterior insula and frontal and parietal operculum. Importantly, all analyses were performed on individual, non-normalized fMRI images. For heat stimuli, we found hand-foot somatotopy in the contralateral anterior and posterior insula [hand, 9 ± 10 (SD) mm anterior to foot, P < 0.05] and in the contralateral parietal operculum (SII; hand, 7 ± 10 mm lateral to foot, P < 0.05). For pinprick stimuli, we also found somatotopy in the contralateral posterior insula (hand, 9 ± 10 mm anterior to foot, P < 0.05). Furthermore, the response to heat stimulation of the hand was 11 ± 12 mm anterior to the response to pinprick stimulation of the hand in the contralateral (left) anterior insula (P < 0.05). These results indicate the existence of multiple somatotopic representations for pain within the operculo-insular region in humans, possibly reflecting its importance as a sensory-integration site that directs emotional responses and behavior appropriately depending on the body site being injured.