Depressive Symptomatology, Racial Discrimination Experience, and Brain Tissue Volumes Observed on Magnetic Resonance Imaging.

Not much is known about brain structural change in younger populations and minorities. The cross-sectional relationship between depressive symptomatology and racial discrimination with structural measures of brain tissue volume was investigated using magnetic resonance images of 710 participants in the Coronary Artery Risk Development in Young Adults CARDIA Study in 2010. Those reporting depressive symptoms and racial discrimination had lower total brain matter volume compared with those who reported neither (-8.8 mL, 95% confidence interval (CI): -16.4, -1.2), those who reported depressive symptoms only (-10.9 mL, 95% CI: -20.4, -1.4), and those who reported racial discrimination only (-8.6 mL, 95% CI: -16.5, -0.8). Results were similar for total normal white matter. There were 103% higher odds (odds ratio = 2.03, 95% CI: 1.32, 3.14) of being in the highest quartile of white matter hyperintensities in those with depressive symptoms only compared to those without. Although tests for interaction by race were not statistically significant, sensitivity analyses stratified by race revealed inverse associations with total brain matter and total white matter volumes only among black participants with combined depressive symptomatology and experience of racial discrimination, and positive associations only among white participants with depressive symptoms with presence of white matter hyperintensities, suggesting future studies may focus on race.

Imaging patterns of brain development and their relationship to cognition.

We present a brain development index (BDI) that concisely summarizes complex imaging patterns of structural brain maturation along a single dimension using a machine learning methodology. The brain was found to follow a remarkably consistent developmental trajectory in a sample of 621 subjects of ages 8-22 participating in the Philadelphia Neurodevelopmental Cohort, reflected by a cross-validated correlation coefficient between chronologic age and the BDI of r = 0.89. Critically, deviations from this trajectory related to cognitive performance. Specifically, subjects whose BDI was higher than their chronological age displayed significantly superior cognitive processing speed compared with subjects whose BDI was lower than their actual age. These results indicate that the multiparametric imaging patterns summarized by the BDI can accurately delineate trajectories of brain development and identify individuals with cognitive precocity or delay.

Neuronal hibernation following hippocampal demyelination.

Cognitive dysfunction occurs in greater than 50% of individuals with multiple sclerosis (MS). Hippocampal demyelination is a prominent feature of postmortem MS brains and hippocampal atrophy correlates with cognitive decline in MS patients. Cellular and molecular mechanisms responsible for neuronal dysfunction in demyelinated hippocampi are not fully understood. Here we investigate a mouse model of hippocampal demyelination where twelve weeks of treatment with the oligodendrocyte toxin, cuprizone, demyelinates over 90% of the hippocampus and causes decreased memory/learning. Long-term potentiation (LTP) of hippocampal CA1 pyramidal neurons is considered to be a major cellular readout of learning and memory in the mammalian brain. In acute slices, we establish that hippocampal demyelination abolishes LTP and excitatory post-synaptic potentials of CA1 neurons, while pre-synaptic function of Schaeffer collateral fibers is preserved. Demyelination also reduced Ca2+-mediated firing of hippocampal neurons in vivo. Using three-dimensional electron microscopy, we investigated the number, shape (mushroom, stubby, thin), and post-synaptic densities (PSDs) of dendritic spines that facilitate LTP. Hippocampal demyelination did not alter the number of dendritic spines. Surprisingly, dendritic spines appeared to be more mature in demyelinated hippocampi, with a significant increase in mushroom-shaped spines, more perforated PSDs, and more astrocyte participation in the tripartite synapse. RNA sequencing experiments identified 400 altered transcripts in demyelinated hippocampi. Gene transcripts that regulate myelination, synaptic signaling, astrocyte function, and innate immunity were altered in demyelinated hippocampi. Hippocampal remyelination rescued synaptic transmission, LTP, and the majority of gene transcript changes. We establish that CA1 neurons projecting demyelinated axons silence their dendritic spines and hibernate in a state that may protect the demyelinated axon and facilitates functional recovery following remyelination.

The neural response to deep brain stimulation of the anterior nucleus of the thalamus: A MEMRI and c-Fos study.

BACKGROUND: Deep brain stimulation (DBS) refers to the delivery of electric current to specific deep brain structures through implanted electrodes. Recently approved for use in United States, DBS to the anterior nucleus of thalamus (ANT) is a safe and effective alternative treatment for medically refractory seizures. Despite the anti-seizure effects of ANT DBS, preclinical and clinical studies have failed to demonstrate it actions at a whole brain level. OBJECTIVE: Here, we used a magnetic resonance imaging (MRI)-based approach in healthy adult rats to investigate the effects of ANT DBS through the circuit of Papez, which has central role in the generation and propagation of limbic seizures, in temporal lobe epilepsy (TLE). METHODS: After ANT electrode implantation and recovery, ANT DBS and SHAM (sham animals had electrodes implanted but were not stimulated) rats received one single injection of the contrast enhancer, manganese chloride (60 mg/kg, ip). Twelve hours after, rats underwent the baseline scan using the MEMRI (Manganese-Enhanced Magnetic Resonance Imaging) technique. We used the same MEMRI and parvalbumin sequence to follow the DBS delivered during 1 h (130 Hz and 200 µA). Perfusion was followed by subsequent c-Fos and parvalbumin immunostaining of brain sections. RESULTS: Acute unilateral ANT DBS significantly reduced the overall manganese uptake and consequently, the MEMRI contrast in the circuit of Papez. Additionally, c-Fos expression was bilaterally increased in the cingulate cortex and posterior hypothalamus, areas directly connected to ANT, as well as in amygdala and subiculum, within the limbic circuitry. CONCLUSION: Our data indicate that MEMRI can be used to detect whole-brain responses to DBS, as the high frequency stimulation parameters used here caused a significant reduction of cell activity in the circuit of Papez that might help to explain the antiepileptic effects of ANT DBS.

Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study.

BACKGROUND: Demyelination of cerebral white matter is thought to drive neuronal degeneration and permanent neurological disability in individuals with multiple sclerosis. Findings from brain MRI studies, however, support the possibility that demyelination and neuronal degeneration can occur independently. We aimed to establish whether post-mortem brains from patients with multiple sclerosis show pathological evidence of cortical neuronal loss that is independent of cerebral white-matter demyelination. METHODS: Brains and spinal cords were removed at autopsy from patients, who had died with multiple sclerosis, at the Cleveland Clinic in Cleveland, OH, USA. Visual examination of centimetre-thick slices of cerebral hemispheres was done to identify brains without areas of cerebral white-matter discoloration that were indicative of demyelinated lesions (referred to as myelocortical multiple sclerosis) and brains that had cerebral white-matter discolorations or demyelinated lesions (referred to as typical multiple sclerosis). These individuals with myelocortical multiple sclerosis were matched by age, sex, MRI protocol, multiple sclerosis disease subtype, disease duration, and Expanded Disability Status Scale, with individuals with typical multiple sclerosis. Demyelinated lesion area in tissue sections of cerebral white matter, spinal cord, and cerebral cortex from individuals classed as having myelocortical and typical multiple sclerosis were compared using myelin protein immunocytochemistry. Neuronal densities in cortical layers III, V, and VI from five cortical regions not directly connected to spinal cord (cingulate gyrus and inferior frontal cortex, superior temporal cortex, and superior insular cortex and inferior insular cortex) were also compared between the two groups and with aged-matched post-mortem brains from individuals without evidence of neurological disease. FINDINGS: Brains and spinal cords were collected from 100 deceased patients between May, 1998, and November, 2012, and this retrospective study was done between Sept 6, 2011, and Feb 2, 2018. 12 individuals were identified as having myelocortical multiple sclerosis and were compared with 12 individuals identified as having typical multiple sclerosis. Demyelinated lesions were detected in spinal cord and cerebral cortex, but not in cerebral white matter, of people with myelocortical multiple sclerosis. Cortical demyelinated lesion area was similar between myelocortical and typical multiple sclerosis (median 4·45% [IQR 2·54-10·81] in myelocortical vs 9·74% [1·35-19·50] in typical multiple sclerosis; p=0·5512). Spinal cord demyelinated area was significantly greater in typical than in myelocortical multiple sclerosis (median 3·81% [IQR 1·72-7·42] in myelocortical vs 13·81% [6·51-29·01] in typical multiple sclerosis; p=0·0083). Despite the lack of cerebral white-matter demyelination in myelocortical multiple sclerosis, mean cortical neuronal densities were significantly decreased compared with control brains (349·8 neurons per mm2 [SD 51·9] in myelocortical multiple sclerosis vs 419·0 [43·6] in controls in layer III [p=0·0104]; 355·6 [46·5] vs 454·2 [48·3] in layer V [p=0·0006]; 366·6 [50·9] vs 458·3 [48·4] in layer VI [p=0·0049]). By contrast, mean cortical neuronal densities were decreased in typical multiple sclerosis brains compared with those from controls in layer V (392·5 [59·0] vs 454·2 [48·3]; p=0·0182) but not layers III and VI. INTERPRETATION: We propose that myelocortical multiple sclerosis is a subtype of multiple sclerosis that is characterised by demyelination of spinal cord and cerebral cortex but not of cerebral white matter. Cortical neuronal loss is not accompanied by cerebral white-matter demyelination and can be an independent pathological event in myelocortical multiple sclerosis. Compared with control brains, cortical neuronal loss was greater in myelocortical multiple sclerosis cortex than in typical multiple sclerosis cortex. The molecular mechanisms of primary neuronal degeneration and axonal pathology in myelocortical multiple sclerosis should be investigated in future studies. FUNDING: US National Institutes of Health and National Multiple Sclerosis Society.

Spatial patterns of structural brain changes in type 2 diabetic patients and their longitudinal progression with intensive control of blood glucose.

OBJECTIVE: Understanding the effect of diabetes as well as of alternative treatment strategies on cerebral structure is critical for the development of targeted interventions against accelerated neurodegeneration in type 2 diabetes. We investigated whether diabetes characteristics were associated with spatially specific patterns of brain changes and whether those patterns were affected by intensive versus standard glycemic treatment. RESEARCH DESIGN AND METHODS: Using baseline MRIs of 488 participants with type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) study, we applied a new voxel-based analysis methodology to identify spatially specific patterns of gray matter and white matter volume loss related to diabetes duration and HbA1c. The longitudinal analysis used 40-month follow-up data to evaluate differences in progression of volume loss between intensive and standard glycemic treatment arms. RESULTS: Participants with longer diabetes duration had significantly lower gray matter volumes, primarily in certain regions in the frontal and temporal lobes. The longitudinal analysis of treatment effects revealed a heterogeneous pattern of decelerated loss of gray matter volume associated with intensive glycemic treatment. Intensive treatment decelerated volume loss, particularly in regions adjacent to those cross-sectionally associated with diabetes duration. No significant relationship between low versus high baseline HbA1c levels and brain changes was found. Finally, regions in which cognitive change was associated with longitudinal volume loss had only small overlap with regions related to diabetes duration and to treatment effects. CONCLUSIONS: Applying advanced quantitative image pattern analysis methods on longitudinal MRI data of a large sample of patients with type 2 diabetes, we demonstrate that there are spatially specific patterns of brain changes that vary by diabetes characteristics and that the progression of gray matter volume loss is slowed by intensive glycemic treatment, particularly in regions adjacent to areas affected by diabetes.

Cardiorespiratory fitness and brain volume and white matter integrity: The CARDIA Study.

OBJECTIVE: We hypothesized that greater cardiorespiratory fitness is associated with lower odds of having unfavorable brain MRI findings. METHODS: We studied 565 healthy, middle-aged, black and white men and women in the CARDIA (Coronary Artery Risk Development in Young Adults) Study. The fitness measure was symptom-limited maximal treadmill test duration (Maxdur); brain MRI was measured 5 years later. Brain MRI measures were analyzed as means and as proportions below the 15th percentile (above the 85th percentile for white matter abnormal tissue volume). RESULTS: Per 1-minute-higher Maxdur, the odds ratio for having less whole brain volume was 0.85 (p = 0.04) and for having low white matter integrity was 0.80 (p = 0.02), adjusted for age, race, sex, clinic, body mass index, smoking, alcohol, diet, physical activity, education, blood pressure, diabetes, total cholesterol, and lung function (plus intracranial volume for white matter integrity). No significant associations were observed between Maxdur and abnormal tissue volume or blood flow in white matter. Findings were similar for associations with continuous brain MRI measures. CONCLUSIONS: Greater physical fitness was associated with more brain volume and greater white matter integrity measured 5 years later in middle-aged adults.

Vascular factors and multiple measures of early brain health: CARDIA brain MRI study.

OBJECTIVE: To identify early changes in brain structure and function that are associated with cardiovascular risk factors (CVRF). DESIGN: Cross-sectional brain Magnetic Resonance I (MRI) study. SETTING: Community based cohort in three U.S. sites. PARTICIPANTS: A Caucasian and African-American sub-sample (n= 680; mean age 50.3 yrs) attending the 25 year follow-up exam of the Coronary Artery Risk Development in Young Adults Study. PRIMARY AND SECONDARY OUTCOMES: 3T brain MR images processed for quantitative estimates of: total brain (TBV) and abnormal white matter (AWM) volume; white matter fractional anisotropy (WM-FA); and gray matter cerebral blood flow (GM-CBF). Total intracranial volume is TBV plus cerebral spinal fluid (TICV). A Global Cognitive Function (GCF) score was derived from tests of speed, memory and executive function. RESULTS: Adjusting for TICV and demographic factors, current smoking was significantly associated with lower GM-CBF and TBV, and more AWM (all <0.05); SA with lower GM-CBF, WM-FA and TBV (p=0.01); increasing BMI with decreasing GM-CBF (p<0003); hypertension with lower GM-CBF, WM-FA, and TBV and higher AWM (all <0.05); and diabetes with lower TBV (p=0.007). The GCS was lower as TBV decreased, AWM increased, and WM-FA (all p<0.01). CONCLUSION: In middle age adults, CVRF are associated with brain health, reflected in MRI measures of structure and perfusion, and cognitive functioning. These findings suggest markers of mid-life cardiovascular and brain health should be considered as indication for early intervention and future risk of late-life cerebrovascular disease and dementia.

Effect of hypoglycemia on brain structure in people with type 2 diabetes: epidemiological analysis of the ACCORD-MIND MRI trial.

OBJECTIVE: The effect of hypoglycemia related to treatment of type 2 diabetes mellitus (T2DM) on brain structure remains unclear. We aimed to assess whether symptomatic severe hypoglycemia is associated with brain atrophy and/or white matter abnormalities. RESEARCH DESIGN AND METHODS: We included T2DM participants with brain MRI from the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) trial. Symptomatic severe hypoglycemia was defined as blood glucose <2.8 mmol/L or symptoms resolved with treatments that required the assistance of another person or medical assistance (hypoglycemia requiring assistance [HA]). Standardized brain MRI was performed at baseline and at 40 months. Total brain volume (TBV) and abnormal white matter (AWM) volume were calculated using an automated computer algorithm. Brain MRI scans of hypoglycemic participants were also reviewed for local disease. RESULTS: Of the 503 T2DM participants (mean age, 62 years) with successful baseline and 40-month brain MRI, 28 had at least one HA episode during the 40-month follow-up. Compared with participants without HA, those with HA had marginally significant less atrophy (less decrease in TBV) from baseline to 40 months (-9.55 [95% CI -15.21, -3.90] vs. -15.38 [95% CI -16.64, -14.12], P = 0.051), and no significant increase of AWM volume (2.06 [95% CI 1.71, 2.49] vs. 1.84 [95% CI 1.76, 1.91], P = 0.247). In addition, no unexpected local signal changes or volume loss were seen on hypoglycemic participants' brain MRI scans. CONCLUSIONS: Our study suggests that hypoglycemia related to T2DM treatment may not accentuate brain pathology, specifically brain atrophy or white matter abnormalities.

Prediction of human voluntary movement before it occurs.

OBJECTIVE: Human voluntary movement is associated with two changes in electroencephalography (EEG) that can be observed as early as 1.5 s prior to movement: slow DC potentials and frequency power shifts in the alpha and beta bands. Our goal was to determine whether and when we can reliably predict human natural movement BEFORE it occurs from EEG signals ONLINE IN REAL-TIME. METHODS: We developed a computational algorithm to support online prediction. Seven healthy volunteers participated in this study and performed wrist extensions at their own pace. RESULTS: The average online prediction time was 0.62±0.25 s before actual movement monitored by EMG signals. There were also predictions that occurred without subsequent actual movements, where subjects often reported that they were thinking about making a movement. CONCLUSION: Human voluntary movement can be predicted before movement occurs. SIGNIFICANCE: The successful prediction of human movement intention will provide further insight into how the brain prepares for movement, as well as the potential for direct cortical control of a device which may be faster than normal physical control.

Single trial detection of human movement intentions from SAM-filtered MEG signals for a high performance two-dimensional BCI.

The objective of this research is to explore whether a two-dimensional BCI can be achieved by reliably decoding single-trial magneto-encephalography (MEG) signal associated with sustaining or ceasing right and left hand movements. Seven naïve subjects participated in the study. Signals were recorded from 275-channel MEG and synthetic aperture magnetometry (SAM) was employed. The multi-class classification for four-directional control was evaluated offline from 10-fold cross-validation using direct-decision tree classifier and genetic algorithm based Mahalanobis linear distance. Beta band (15-30Hz) event-related desynchronization and event related synchronization were observed in right and left hand movement related motor areas for physical movements as well as motor imagery. The cross-validation accuracy for the proposed four-direction classification from SAM- filtered MEG signal was as high as 95-97% for physical movements and 86-87% for motor imagery. The high classification accuracy suggests that a reliable high performance two-dimensional BCI can be achieved from single trial detection of human natural movement intentions from SAM-filtered MEG signals, where user may not need extensive training.

Spatial detection of multiple movement intentions from SAM-filtered single-trial MEG signals.

OBJECTIVE: To test whether human intentions to sustain or cease movements in right and left hands can be decoded reliably from spatially filtered single-trial magnetoencephalographic (MEG) signals for motor execution and motor imagery. METHODS: Seven healthy volunteers, naïve to BCI technology, participated in this study. Signals were recorded from 275-channel MEG, and synthetic aperture magnetometry (SAM) was employed as the spatial filter. The four-class classification was performed offline. Genetic algorithm based Mahalanobis linear distance (GA-MLD) and direct-decision tree classifier (DTC) techniques were adopted for the classification through 10-fold cross-validation. RESULTS: Through SAM imaging, strong and distinct event-related desynchronization (ERD) associated with sustaining, and event-related synchronization (ERS) patterns associated with ceasing of right and left hand movements were observed in the beta band (15-30Hz) on the contralateral hemispheres for motor execution and motor imagery sessions. Virtual channels were selected from these areas of high activity for the corresponding events as per the paradigm of the study. Through a statistical comparison between SAM-filtered virtual channels from single-trial MEG signals and basic MEG sensors, it was found that SAM-filtered virtual channels significantly increased the classification accuracy for motor execution (GA-MLD: 96.51+/-2.43%) as well as motor imagery sessions (GA-MLD: 89.69+/-3.34%). CONCLUSION: Multiple movement intentions can be reliably detected from SAM-based spatially filtered single-trial MEG signals. SIGNIFICANCE: MEG signals associated with natural motor behavior may be utilized for a reliable high-performance brain-computer interface (BCI) and may reduce long-term training compared with conventional BCI methods using rhythm control.