MRI and diffusion tensor imaging in assessing correlation of activation of cortical motor function and manifestations of corticospinal tract with muscle strength in patients with ischemic stroke

IN T R O D U C T IO N Ischem ic stroke is often follow ed by the abnorm alities ofneurons and corticospinaltract,w hich lead to corresponding clinicalsym ptom s and signs. R ecently, w ith the continuous perfection ofhigh-field M R Iin- strum ent, itis po…     

Long-term sequelae of herpes simplex virus encephalitis–related white matter injury: correlation of neuropsychological outcome and diffusion tensor imaging

Journal of NeuroVirology - The pathophysiology of the memory impairment following Herpes Simplex virus encephalitis is not yet established and understood. This study attempts to elucidate the role...     

Characters of MR diffusion tensor imaging in cerebral ischemic corticospinal tract injury

BACKGROUND: Diffusion tensor imaging (DTI) is one of the noninvasive methods to study the morphological structure of brain white matter fibrous bands in vivo, and it has been applied primarily in clinic. DTI is acknowledged as the more effective imaging method to diagnose ultra-acute and/or acute cerebral infarction. OBJECTIVE: To observe the anisotropic characters of cerebral white matter fibrous bands in patients with ischemic stroke by using DTI, and investigate the correlation between the damage of corticospinal tract and muscle strength in patients with ischemic stroke at acute period. DESIGN: A case-control observation. SETTING: Department of Medical Imaging, Fuzhou General Hospital of Nanjing Military Area Command of Chinese PLA. PARTICIPANTS: Nine inpatients with injury of motor function induced by acute ischemic stroke (patient group) at 6 hours to 2 weeks after the attack were selected from the Department of Neurology, Fuzhou General Hospital of Nanjing Military Area Command of Chinese PLA from September 2005 to March 2006, and they all accorded with the present diagnostic standard for cerebrovascular disease in China. There were 5 males and 4 females, aged 16-87 years. At the same time, nine healthy right-handed physical examinees matched by age and sex with the patients were taken as the control group, and they all had no nervous disease, mental diseases, cerebrovascular abnormalities and injury history, etc. All the subjects were informed with the detected items and agreed to participate in the study. METHODS: All the 9 patients with ischemic stroke at acute period and 9 healthy subjects were examined with MRI, T1 weighted imaging, T2 weighted imaging and DTI. And the data were processed offline with dTV.II software, the images of fractional anisotropy and directional encoded color (DEC) were obtained, and the three-dimensional fibrous band images of bilateral corticospinal tracts were reconstructed. In the control group, the values of fractional anisotropy of main white matter fibrous bands were measured in the region of interest (ROI) of the anterior limb, knee and posterior limb of internal capsule. In the patient group, the values of fractional anisotropy of white matter were measured in the infarcted sites and corresponding contralateral sites of the patients. The ROI was set in bilateral cerebral peduncles to reconstruct three-dimensionally the bilateral corticospinal tracts. The muscle strength of the affected hand was assessed with Brunnstorm standard in the stroke patients. MAIN OUTCOME MEASURES: The characters of DTI and images of the value of fractional anisotropy, and the manifestations of three-dimensional corticospinal tracts were observed in the two groups. RESULTS: All the data from the 9 patients and 9 healthy volunteers were involved in the analysis of results. ① In the control group, the white matter and gray matter could be distinguished clearly in the image of fractional anisotropic values, the fibers of different directions were shown by different colors in DEC picture, which clearly demonstrated the normal anatomic structure and direction of white matter fibers. In the patient group, the infarctions occurred in the gray matter or white matter could be distinguished in the images of fractional anisotropic values, DEC picture could clearly show the direct influence of the infarcted site on the white matter fibers. The fractional anisotropic values in different white matter structure of the same side were significantly different in the control group (t =3.12, P < 0.05), and the reconstructed images fractional anisotropic values and DEC picture could show most of the main white matter fibrous bands. The fractional anisotropic values of the infarcted sites were significantly lower than the contralateral ones in the patient group (t=5.570, P < 0.01). ② The reconstructed bilateral corticospinal tracts showed that the anatomic forms of the contralateral corticospinal tract of the patients were almost identical to those of normal people, it started from precentral gyrus, downward to the nternal capsule, and extended to pontine and medulla oblongata, each fibrous band was continuous, and the form had good consistency. Because of the involvement of infarction of different severity, the ipsilateral corticospinal tract manifested as continuous interruption and the loss of consistent anatomic structural form. The involved severity of corticospinal tract had significant correlation with that of muscle strength of the ipsilateral hand (r =1.30, P < 0.01). CONCLUSION: ① DTI can display the direction and distribution of cerebral white matter fibrous bands. ② DTI images of fractional anisotropic values and DEC can show the directions and anisotropic degree of white matter fibers in the infarcted sites of stroke patients. ③ The three-dimensional images of fibrous bands can show the conditions of pyramidal tracts more directly. ④ The damaged severity of corticospinal tracts is correlated with that of muscle strength.     

Monitoring stroke progression: in vivo imaging of cortical perfusion,blood–brain barrier permeability and cellular damage in the rat photothrombosis model

Focal cerebral ischemia is among the main causes of death and disability worldwide. The ischemic core often progresses, invading the peri-ischemic brain; however, assessing the propensity of the peri-ischemic brain to undergo secondary damage, understanding the underlying mechanisms, and adjusting treatment accordingly remain clinically unmet challenges. A significant hallmark of the peri-ischemic brain is dysfunction of the blood–brain barrier (BBB), yet the role of disturbed vascular permeability in stroke progression is unclear. Here we describe a longitudinal in vivo fluorescence imaging approach for the evaluation of cortical perfusion, BBB dysfunction, free radical formation and cellular injury using the photothrombosis vascular occlusion model in male Sprague Dawley rats. Blood–brain barrier dysfunction propagated within the peri-ischemic brain in the first hours after photothrombosis and was associated with free radical formation and cellular injury. Inhibiting free radical signaling significantly reduced progressive cellular damage after photothrombosis, with no significant effect on blood flow and BBB permeability. Our approach allows a dynamic follow-up of cellular events and their response to therapeutics in the acutely injured cerebral cortex.     

Is depression a disconnection syndrome? Meta-analysis of diffusion tensor imaging studies in patients with MDD

Background: Many studies using diffusion tensor imaging (DTI) have demonstrated impaired white matter integrity in patients with major depressive disorder (MDD), with significant results found in diverse brain regions. We sought to identify whether there are consistent changes of regional white matter integrity in patients with MDD, as shown by decreased fractional anisotropy in DTI. Method: A systematic search strategy was used to identify relevant whole brain voxel-based DTI studies of patients with MDD in relation to comparison groups. Relevant databases were searched for studies published between January 1994 and February 2011 using combinations of the terms "DTI" or "diffusion tensor;" "whole brain" or "voxel-based;" and "depress*." Using the studies that met our inclusion criteria, we performed a meta-analysis of the coordinates of decreased fractional anisotropy using the activation likelihood estimation (ALE) method, which detects 3-dimensional conjunctions of coordinates from multiple studies, weighted by sample size. We then used DTIquery software for fibre tracking to locate the fascicles involved in each region. Results: We included 11 studies with a combined sample of 231 patients with MDD and 261 comparison participants, providing 50 coordinates of decreased fractional anisotropy. Our meta-analysis identified 4 consistent locations of decreased fractional anisotropy in patients with MDD: white matter in the right frontal lobe, right fusiform gyrus, left frontal lobe and right occipital lobe. Fibre tracking showed that the main fascicles involved were the right inferior longitudinal fasciculus, right inferior fronto-occipital fasciculus, right posterior thalamic radiation and interhemispheric fibres running through the genu and body of the corpus callosum. Limitations: The number of studies included was relatively small, and the DTI data acquisition and analysis techniques were heterogeneous. The ALE method cannot handle studies with no significant group differences. Conclusion: Voxel-based analysis of DTI studies of patients with MDD consistently identified decreased fractional anisotropy in the white matter fascicles connecting the prefrontal cortex within cortical (frontal, temporal and occipital lobes) and subcortical areas (amygdala and hippocampus). This isstrong evidence for the involvement of these neural circuits in the pathology of MDD.     

Is depression a disconnection syndrome? Meta-analysis of diffusion tensor imaging studies in patients with MDD

Background

Many studies using diffusion tensor imaging (DTI) have demonstrated impaired white matter integrity in patients with major depressive disorder (MDD), with significant results found in diverse brain regions. We sought to identify whether there are consistent changes of regional white matter integrity in patients with MDD, as shown by decreased fractional anisotropy in DTI.

Method

A systematic search strategy was used to identify relevant whole brain voxel-based DTI studies of patients with MDD in relation to comparison groups. Relevant databases were searched for studies published between January 1994 and February 2011 using combinations of the terms “DTI” or “diffusion tensor;” “whole brain” or “voxel-based;” and “depress^*.” Using the studies that met our inclusion criteria, we performed a meta-analysis of the coordinates of decreased fractional anisotropy using the activation likelihood estimation (ALE) method, which detects 3-dimensional conjunctions of coordinates from multiple studies, weighted by sample size. We then used DTIquery software for fibre tracking to locate the fascicles involved in each region.

Results

We included 11 studies with a combined sample of 231 patients with MDD and 261 comparison participants, providing 50 coordinates of decreased fractional anisotropy. Our meta-analysis identified 4 consistent locations of decreased fractional anisotropy in patients with MDD: white matter in the right frontal lobe, right fusiform gyrus, left frontal lobe and right occipital lobe. Fibre tracking showed that the main fascicles involved were the right inferior longitudinal fasciculus, right inferior fronto-occipital fasciculus, right posterior thalamic radiation and interhemispheric fibres running through the genu and body of the corpus callosum.

Limitations

The number of studies included was relatively small, and the DTI data acquisition and analysis techniques were heterogeneous. The ALE method cannot handle studies with no significant group differences.

Conclusion

Voxel-based analysis of DTI studies of patients with MDD consistently identified decreased fractional anisotropy in the white matter fascicles connecting the prefrontal cortex within cortical (frontal, temporal and occipital lobes) and subcortical areas (amygdala and hippocampus). This is strong evidence for the involvement of these neural circuits in the pathology of MDD.     

Age-related changes of lateral ventricular width and periventricular white matter in the human brain： a diffusion tensor imaging study

<正>Introduction Aging is the accumulation of multidimensional deterioration of processing of biological,psychological,and social changes with expansion over time(Bowen and Atwood,2004;Grady,2012).Aging-related changes are typically accompanied by decline in cognitive function,urinary control,sensory-motor function,and gait ability(Bradley et al.,1991;Bowen and Atwood,2004;Hedden and Gabrieli,2004;Grady,2012;Moran et al.,     

Prenatal stress and limbic-prefrontal white matter microstructure in children aged 6–9 years: a preliminary diffusion tensor imaging study

Objectives. Maternal prenatal stress is associated with elevated risk of adverse behavioural outcomes in offspring. This association may involve developmental disruption to limbic-prefrontal white matter circuitry, of which the uncinate fasciculus is the major tract. One potential candidate for modulating brain development is maternal prenatal stress. We provide the first prospective study of prenatal stress and white matter microstructure in children. Methods. A total of 22 healthy children (mean age 7 years) of mothers recruited in pregnancy underwent diffusion tensor magnetic resonance imaging. We examined correlations between prenatal stressful life events and white matter microstructural organisation indices (fractional anisotropy (FA) and perpendicular diffusivity (D_perp)) of the uncinate fasciculus and a “control” tract. Results. Maternal prenatal stressful life events were correlated positively with right uncinate fasciculus FA, and negatively with right uncinate fasciculus D_perp in their child, with a similar trend with left uncinate fasciculus D_perp. Prenatal stress was not associated with control tract properties; sociodemographic/obstetric variables were not associated with FA/D_perp of either tract. Conclusions. Variation in maternal prenatal stress may be associated with differences in the development of white matter within brain networks underlying child social behaviour.     

Fluoxetine ameliorates behavioral and neuropathological deficits in a transgenic model mouse of α-synucleinopathy

The term α-synucleinopathies refers to a group of age-related neurological disorders including Parkinson's disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) that display an abnormal accumulation of alpha-synuclein (α-syn). In contrast to the neuronal α-syn accumulation observed in PD and DLB, MSA is characterized by a widespread oligodendrocytic α-syn accumulation. Transgenic mice expressing human α-syn under the oligodendrocyte-specific myelin basic protein promoter (MBP1-hαsyn tg mice) model many of the behavioral and neuropathological alterations observed in MSA. Fluoxetine, a selective serotonin reuptake inhibitor, has been shown to be protective in toxin-induced models of PD, however its effects in an in vivo transgenic model of α-synucleinopathy remain unclear. In this context, this study examined the effect of fluoxetine in the MBP1-hαsyn tg mice, a model of MSA. Fluoxetine administration ameliorated motor deficits in the MBP1-hαsyn tg mice, with a concomitant decrease in neurodegenerative pathology in the basal ganglia, neocortex and hippocampus. Fluoxetine administration also increased levels of the neurotrophic factors, GDNF (glial-derived neurotrophic factor) and BDNF (brain-derived neurotrophic factor) in the MBP1-hαsyn tg mice compared to vehicle-treated tg mice. This fluoxetine-induced increase in GDNF and BDNF protein levels was accompanied by activation of the ERK signaling pathway. The effects of fluoxetine administration on myelin and serotonin markers were also examined. Collectively these results indicate that fluoxetine may represent a novel therapeutic intervention for MSA and other neurodegenerative disorders.     

Head injury or head motion? Assessment and quantification of motion artifacts in diffusion tensor imaging studies

The relationship between head motion and diffusion values such as fractional anisotropy (FA) and mean diffusivity (MD) is currently not well understood. Simulation studies suggest that head motion may introduce either a positive or negative bias, but this has not been quantified in clinical studies. Moreover, alternative measures for removing bias as result of head motion, such as the removal of problematic gradients, has been suggested but not carefully evaluated. The current study examined the impact of head motion on FA and MD across three common pipelines (tract-based spatial statistics, voxelwise, and region of interest analyses) and determined the impact of removing diffusion weighted images. Our findings from a large cohort of healthy controls indicate that while head motion was associated with a positive bias for both FA and MD, the effect was greater for MD. The positive bias was observed across all three analysis pipelines and was present following established protocols for data processing, suggesting that current techniques (i.e., correction of both image and gradient table) for removing motion bias are likely insufficient. However, the removal of images with gross artifacts did not fundamentally change the relationship between motion and DTI scalar values. In addition, Monte Carlo simulations suggested that the random removal of images increases the bias and reduces the precision of both FA and MD. Finally, we provide an example of how head motion can be quantified across different neuropsychiatric populations, which should be implemented as part of any diffusion tensor imaging quality assurance protocol.     

Longitudinal,region-specific course of diffusion tensor imaging measures in mild cognitive impairment and Alzheimer’s disease

BackgroundDiffusion tensor imaging (DTI) is a promising method for identifying significant cross-sectional differences of white-matter tracts in normal controls (NC) and those with mild cognitive impairment (MCI) or Alzheimer’s disease (AD). There have not been many studies establishing its longitudinal utility.MethodsSeventy-five participants (25 NC, 25 amnestic MCI, and 25 AD) had 3-Tesla MRI scans and clinical evaluations at baseline and 3, 6, and 12 months. Fractional anisotropy (FA) and mean diffusivity (MD) were analyzed at each time-point and longitudinally in eight a priori–selected areas taken from four regions of interest (ROIs).ResultsCross-sectionally, MD values were higher, and FA values lower in the fornix and splenium of the AD group compared with either MCI or NC (P < .01). Within-group change was more evident in MD than in FA over 12 months: MD increased in the inferior, anterior cingulum, and fornix in both the MCI and AD groups (P < .01).ConclusionsThere were stable, cross-sectional, region-specific differences between the NC and AD groups in both FA and MD at each time-point over 12 months. Longitudinally, MD was a better indicator of change than FA. Significant increases of fornix MD in the MCI group suggest this is an early indicator of progression.     

Microstructural changes in the hippocampus and posterior cingulate in mild cognitive impairment and Alzheimer’s disease: a diffusion tensor imaging study

Diffusion tensor imaging (DTI) is a sensitive MRI technique in the detection of white matter degeneration. We sought to demonstrate microstructural changes in normal controls, patients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) and to determine which DTI parameters could be a reliable tool for the early diagnosis of AD. In total, 90 participants (35 normal, 20 aMCI, 35 AD) were recruited. We included early AD patients with clinical dementia rating scores of 0.5 and 1. The fractional anisotropy and mean diffusivity values, DTI parameter, were measured with the regions of interest method in the bilateral hippocampal body and posterior cingulate. Clinical history, neurological examination, and neuropsychological assessments were conducted. The DTI parameters in the bilateral hippocampus and posterior cingulate in aMCI and AD were different from those in normal controls. No difference was found in DTI parameters of the posterior cingulate between aMCI and AD. However, hippocampal DTI parameters were different between aMCI and AD. Cognitive summary measures were significantly correlated with DTI parameters, especially FA values in the hippocampus. The DTI analysis technique demonstrated significant microstructural alterations in the hippocampus and posterior cingulate already in prodromal stage of AD. DTI parameters in the hippocampus may be a more sensitive method to determine microstructural changes in early AD states and more correlated with cognition than DTI parameters in the posterior cingulate.     

Developmental process of the arcuate fasciculus from infancy to adolescence：a diffusion tensor imaging study

We investigated the radiologic developmental process of the arcuate fasciculus(AF) using subcomponent diffusion tensor imaging(DTI) analysis in typically developing volunteers. DTI data were acquired from 96 consecutive typically developing children, aged 0–14 years. AF subcomponents, including the posterior, anterior, and direct AF tracts were analyzed. Success rates of analysis(AR) and fractional anisotropy(FA) values of each subcomponent tract were measured and compared. AR of all subcomponent tracts, except the posterior, showed a significant increase with aging(P 0.05). Subcomponent tracts had a specific developmental sequence: First, the posterior AF tract, second, the anterior AF tract, and last, the direct AF tract in identical hemispheres. FA values of all subcomponent tracts, except right direct AF tract, showed correlation with subject's age(P 0.05). Increased AR and FA values were observed in female subjects in young age(0–2 years) group compared with males(P 0.05). The direct AF tract showed leftward hemispheric asymmetry and this tendency showed greater consolidation in older age(3–14 years) groups(P 0.05). These findings demonstrated the radiologic developmental patterns of the AF from infancy to adolescence using subcomponent DTI analysis. The AF showed a specific developmental sequence, sex difference in younger age, and hemispheric asymmetry in older age.     

Diffusion tensor imaging depicting damage to the arcuate fasciculus in patients with conduction aphasia: a study of the Wernicke–Geschwind model

Abstract

Objectives: In contrast with disorders of comprehension and spontaneous expression, conduction aphasia is characterized by poor repetition, which is a hallmark of the syndrome. There are many theories on the repetition impairment of conduction aphasia. The disconnection theory suggests that a damaged in the arcuate fasciculus, which connects Broca's and Wernicke's area, is the cause of conduction aphasia. In this study, we examined the disconnection theory.

Methods: We enrolled ten individuals with conduction aphasia and ten volunteers, and analysed their arcuate fasciculus using diffusion tensor imaging (DTI) and obtained fractional anisotropy (FA) values. Then, the results of the left hemisphere were compared with those of the right hemisphere, and the results of the conduction aphasia cases were compared with those of the volunteers.

Results: There were significant differences in the FA values between the left and right hemispheres of volunteers and conduction cases. In volunteers, there was an increase in fiber in the left hemisphere compared with the right hemisphere, whereas there was an increase in fiber in the right hemisphere compared with the left hemisphere in conduction aphasia patients. The results of diffusion tensor tractography suggested that the configuration of the arcuate fasciculus was different between conduction aphasia patients and volunteers, suggesting that there was damage to the arcuate fasciculus of conduction aphasia cases.

Conclusions: The damage seen in the arcuate fasciculus of conduction aphasia cases in this study supports the Wernicke–Geschwind disconnection theory. A disconnection between Broca's area and Wernicke's area is likely to be one mechanism of conduction aphasia repetition impairment.     

Can diffusion tensor imaging and tractography represent cross‐sectional area of lumbar multifidus in patients with LUMBAR spine disease?

Introduction: Cross‐sectional area (CSA) is a useful measurement to evaluate the lumbar multifidus, but it cannot reflect the morphological characteristics of the entire muscle. Recently, diffusion tensor imaging (DTI) and tractography (DTT) have been used to assess 3‐dimensional muscle structures both qualitatively and quantitatively. In this study we investigate the correlation between CSA and multifidus volume and the clinical utility of DTI and DTT. Methods: Twenty‐eight lumbar multifidi from 14 subjects with lumbar spine disease were analyzed. We conducted correlation analysis between CSA from conventional magnetic resonance images and DTI‐derived parameters, including muscle volume, fractional anisotropy (FA), and mean diffusivity (MD); we performed morphological assessment using DTT. Results: Multifidus volume had a strong positive correlation with CSA (r = 0.760, P < 0.001). Neither FA nor MD correlated with CSA. Multifidi spanning fewer vertebral segments were smaller in volume. Discussion: DTT can be a valuable tool to visualize and quantify the lumbar multifidus in lumbar spine disease. Muscle Nerve 57 : 200–205, 2018     

Changes in brain function and anatomical structure following treatment of hyperbaric oxygen for visual pathway abnormalities in 16 cases★ Evaluation of functional magnetic resonance imaging combined with diffusion tensor imaging

BACKGROUND： There is a growing research focus on the combination of blood oxygenation level dependent functional magnetic resonance imaging （BOLD-fMRI） and diffusion tensor imaging （DTI） to evaluate visual cortical function and structural changes in the cerebrum, as well as morphological changes to the white matter fiber tracks, after visual pathway lesions. However, the combined application of BOLD-fMRI and DTI in treating of visual pathway abnormalities still requires further studies.
OBJECTIVE： To observe and evaluate the effects of hyperbaric oxygen on visual pathway abnormalities, and to evaluate the characteristics of cerebral function and anatomic structural changes by using BOLD-fMRI combined with DTI technique. DESIGN： Case contrast observation.
SETTING： Fuzhou General Hospital of Nanjing Military Area Command of Chinese PLA.
PARTICIPANTS： Sixteen patients （9 males and 7 females, 15-77 years old） with lateral or bilateral visual disorder induced by visual pathway lesions were selected from the Department of Neurology, Fuzhou General Hospital of Nanjing Military Area Command of Chinese PLA from January 2006 to May 2007. These patients comprised the lesion group. Measures of interventional therapy： hyperbaric oxygen of two normal atmospheres for three courses （10 d/course） and routine internal medicine treatment. In addition, 12 healthy subjects of similar sex and age to the lesion group were regarded as the control group. The control group underwent routine ophthalmological and ocular fundus examinations; diagnostic results were normal. The experiment received confirmed consent from the local ethic committee, and all patients provided informed consent.
METHODS： BOLD-fMRI and DTI manifestations in the lesion group were observed before and after hyperbaric oxygen intervention, and the results were compared with the control group. The subjects were positioned on their back, and BOLD-fMRI images were collected with the following GRE EPI sequence： TR = 2 000 ms, TE = 40     

Correlation between cognitive function and the association fibers in patients with Alzheimer’s disease using diffusion tensor imaging

White matter (WM) changes, along with well-characterized cortical abnormalities, occur in patients with Alzheimer’s disease (AD). We investigated the integrity of WM tracts within association fibers by the use of fractional anisotropy (FA), and the relationship between FA values and cognitive function in patients with AD. Neuropsychological examination and conventional MRI, as well as diffusion tensor imaging, (DTI) were conducted on 12 patients with mild to moderate AD and 18 cognitively healthy volunteers. DTI was performed to measure FA in the bilateral inferior fronto-occipital fasciculus (IFOF) and the superior longitudinal fasciculus (SLF). Mini-Mental State Examination (MMSE) scores and Montreal Cognitive Assessment (MoCA) values were used to evaluate cognitive function and the Clinical Dementia Rating (CDR) scale was used as a staging tool for dementia severity. FA measures were analyzed and correlated with neuropsychological data. No patient showed any WM tract abnormality on either T1-weighted or T2-weighted MRI. However, the FA values in the bilateral IFOF and SLF and the MoCA scores in patients with AD were significantly decreased (p < 0.05) compared to the controls. Furthermore, the decreased FA values in the SLF were positively correlated with cognitive function (MMSE scores – right: r = 0.672, p = 0.033, left: r = 0.919, p < 0.01; MoCA values – right: r = 0.747, p = 0.013, left: r = 0.679, p = 0.031). Our findings confirmed that the loss of integrity of microstructural WM connectivity has a role in the cognitive decline of patients with AD. The data also suggest that the FA values of the SLF may be used as a clinical marker of cognitive function.