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1.  Quantitative Magnetic Resonance Imaging of Cortical Multiple Sclerosis Pathology 
Although significant improvements have been made regarding the visualization and characterization of cortical multiple sclerosis (MS) lesions using magnetic resonance imaging (MRI), cortical lesions (CL) continue to be under-detected in vivo, and we have a limited understanding of the causes of GM pathology. The objective of this study was to characterize the MRI signature of CLs to help interpret the changes seen in vivo and elucidate the factors limiting their visualization. A quantitative 3D high-resolution (350 μm isotropic) MRI study at 3 Tesla of a fixed post mortem cerebral hemisphere from a patient with MS is presented in combination with matched immunohistochemistry. Type III subpial lesions are characterized by an increase in T1, T2 and M0, and a decrease in MTR in comparison to the normal appearing cortex (NAC). All quantitative MR parameters were associated with cortical GM myelin content, while T1 showed the strongest correlation. The histogram analysis showed extensive overlap between CL and NAC for all MR parameters and myelin content. This is due to the poor contrast in myelin content between CL and NAC in comparison to the variability in myelo-architecture throughout the healthy cortex. This latter comparison is highlighted by the representation of T1 times on cortical surfaces at several laminar depths.
doi:10.1155/2012/742018
PMCID: PMC3506905  PMID: 23213531
2.  Diffusion tensor imaging of post mortem multiple sclerosis brain 
Neuroimage  2007;35(2):467-477.
Magnetic resonance imaging (MRI) is being used to probe the central nervous system (CNS) of patients with multiple sclerosis (MS), a chronic demyelinating disease. Conventional T2-weighted MRI (cMRI) largely fails to predict the degree of patients' disability. This shortcoming may be due to poor specificity of cMRI for clinically relevant pathology. Diffusion tensor imaging (DTI) has shown promise to be more specific for MS pathology. In this study we investigated the association between histological indices of myelin content, axonal count and gliosis, and two measures of DTI (mean diffusivity [MD] and fractional anisotropy [FA]), in unfixed post mortem MS brain using a 1.5-T MR system. Both MD and FA were significantly lower in post mortem MS brain compared to published data acquired in vivo. However, the differences of MD and FA described in vivo between white matter lesions (WMLs) and normal-appearing white matter (NAWM) were retained in this study of post mortem brain: average MD in WMLs was 0.35 × 10− 3 mm2/s (SD, 0.09) versus 0.22 (0.04) in NAWM; FA was 0.22 (0.06) in WMLs versus 0.38 (0.13) in NAWM. Correlations were detected between myelin content (Trmyelin) and (i) FA (r = − 0.79, p < 0.001), (ii) MD (r = 0.68, p < 0.001), and (iii) axonal count (r = − 0.81, p < 0.001). Multiple regression suggested that these correlations largely explain the apparent association of axonal count with (i) FA (r = 0.70, p < 0.001) and (ii) MD (r = − 0.66, p < 0.001). In conclusion, this study suggests that FA and MD are affected by myelin content and – to a lesser degree – axonal count in post mortem MS brain.
doi:10.1016/j.neuroimage.2006.12.010
PMCID: PMC1892244  PMID: 17258908
3.  Diffusion Tensor Imaging of Post Mortem Multiple Sclerosis Brain 
NeuroImage  2006;35(2):467-477.
Magnetic resonance imaging (MRI) is being used to probe the central nervous system (CNS) of patients with multiple sclerosis (MS), a chronic demyelinating disease. Conventional T2-weighted MRI (cMRI) largely fails to predict the degree of patients' disability. This shortcoming may be due to poor specificity of cMRI for clinically relevant pathology. Diffusion tensor imaging (DTI) has shown promise to be more specific for MS pathology. In this study we investigated the association between histological indices of myelin content, axonal count and gliosis, and two measures of DTI (mean diffusivity [MD] and fractional anisotropy [FA]), in unfixed post mortem MS brain using a 1.5-T MR system. Both MD and FA were significantly lower in post mortem MS brain compared to published data acquired in vivo. However, the differences of MD and FA described in vivo between white matter lesions (WMLs) and normal-appearing white matter (NAWM) were retained in this study of post mortem brain: average MD in WMLs was 0.35×10−3 mm2/s (SD, 0.09) versus 0.22 (0.04) in NAWM; FA was 0.22 (0.06) in WMLs versus 0.38 (0.13) in NAWM. Correlations were detected between myelin content (Trmyelin) and (i) FA (r=−0.79, p<0.001), (ii) MD (r=0.68, p<0.001), and (iii) axonal count (r=−0.81, p<0.001). Multiple regression suggested that these correlations largely explain the apparent association of axonal count with (i) FA (r=0.70, p<0.001) and (ii) MD (r=−0.66, p<0.001). In conclusion, this study suggests that FA and MD are affected by myelin content and – to a lesser degree – axonal count in post mortem MS brain.
doi:10.1016/j.neuroimage.2006.12.010
PMCID: PMC1892244  PMID: 17258908
4.  Circuits for multisensory integration and attentional modulation through the prefrontal cortex and the thalamic reticular nucleus in primates 
Reviews in the neurosciences  2007;18(6):417-438.
Converging evidence from anatomic and physiologic studies suggests that the interaction of high-order association cortices with the thalamus is necessary to focus attention on a task in a complex environment with multiple distractions. Interposed between the thalamus and cortex, the inhibitory thalamic reticular nucleus intercepts and regulates communication between the two structures. Recent findings demonstrate that a unique circuitry links the prefrontal cortex with the reticular nucleus and may underlie the process of selective attention to enhance salient stimuli and suppress irrelevant stimuli in behavior. Unlike other cortices, some prefrontal areas issue widespread projections to the reticular nucleus, extending beyond the frontal sector to the sensory sectors of the nucleus and may influence the flow of sensory information from the thalamus to the cortex. Unlike other thalamic nuclei, the mediodorsal nucleus, which is the principal thalamic nucleus for the prefrontal cortex, has similarly widespread connections with the reticular nucleus. Unlike sensory association cortices, some terminations from prefrontal areas to the reticular nucleus are large, suggesting efficient transfer of information. We propose a model showing that the specialized features of prefrontal pathways in the reticular nucleus may allow selection of relevant information and override distractors, in processes that are deranged in schizophrenia.
PMCID: PMC2855189  PMID: 18330211
corticothalamic projections; dual mode of termination; drivers and modulators; inhibitory control; overlap of terminations; mediodorsal nucleus; association cortices
5.  Validity of large-deformation high dimensional brain mapping of the basal ganglia in adults with Tourette syndrome 
Psychiatry research  2007;154(2):181-190.
The basal ganglia and thalamus may play a critical role for behavioral inhibition mediated by prefrontal, parietal, temporal, and cingulate cortices. The cortico-basal ganglia-thalamo-cortical loop with projections from frontal cortex to striatum, then to globus pallidus or to substantia nigra pars reticulata, to thalamus and back to cortex, provides the anatomical substrate for this function. In-vivo neuroimaging studies have reported reduced volumes in the thalamus and basal ganglia in individuals with Tourette Syndrome (TS) when compared with healthy controls. However, patterns of neuroanatomical shape that may be associated with these volume differences have not yet been consistently characterized. Tools are being developed at a rapid pace within the emerging field of computational anatomy that allow for the precise analysis of neuroanatomical shape derived from magnetic resonance (MR) images, and give us the ability to characterize subtle abnormalities of brain structures that were previously undetectable. In this study, T1-weighted MR scans were collected in 15 neuroleptic-naïve adults with TS or chronic motor tics and 15 healthy, tic-free adult subjects matched for age, gender and handedness. We demonstrated the validity and reliability of large-deformation high dimensional brain mapping (HDBM-LD) as a tool to characterize the basal ganglia (caudate, globus pallidus and putamen) and thalamus. We found no significant volume or shape differences in any of the structures in this small sample of subjects.
doi:10.1016/j.pscychresns.2006.08.006
PMCID: PMC2859464  PMID: 17289354
Shape; Reliability; Diffeomorphism
6.  Topography of connections between human prefrontal cortex and mediodorsal thalamus studied with diffusion tractography 
Neuroimage  2010;51(2):555-564.
Studies in monkeys show clear anatomical and functional distinctions among networks connecting with subregions within the prefrontal cortex. Three such networks are centered on lateral orbitofrontal cortex, medial frontal and cingulate cortex, and lateral prefrontal cortex and all have been identified with distinct cognitive roles. Although these areas differ in a number of their cortical connections, some of the first anatomical evidence for these networks came from tracer studies demonstrating their distinct patterns of connectivity with the mediodorsal (MD) nucleus of the thalamus. Here, we present evidence for a similar topography of MD thalamus prefrontal connections, using non-invasive imaging and diffusion tractography (DWI–DT) in human and macaque. DWI–DT suggested that there was a high probability of interconnection between medial MD and lateral orbitofrontal cortex, between caudodorsal MD and medial frontal/cingulate cortex, and between lateral MD and lateral prefrontal cortex, in both species. Within the lateral prefrontal cortex a dorsolateral region (the principal sulcus in the macaque and middle frontal gyrus in the human) was found to have a high probability of interconnection with the MD region between the regions with a high probability of interconnection with other parts of the lateral prefrontal cortex and with the lateral orbitofrontal cortex. In addition to suggesting that the thalamic connectivity in the macaque is a good guide to human prefrontal cortex, and therefore that there are likely to be similarities in the cognitive roles played by the prefrontal areas in both species, the present results are also the first to provide insight into the topography of projections of an individual thalamic nucleus in the human brain.
doi:10.1016/j.neuroimage.2010.02.062
PMCID: PMC2877805  PMID: 20206702
Anatomy; DTI; Human; Macaque; Thalamus
7.  Purkinje Cell Loss in Experimental Autoimmune Encephalomyelitis 
NeuroImage  2009;48(4):637-651.
Gray matter atrophy observed by brain MRI is an important correlate to clinical disability and disease duration in multiple sclerosis. The objective of this study was to link brain atrophy visualized by neuroimaging to its underlying neuropathology using the MS model, experimental autoimmune encephalomyelitis (EAE). Volumetric changes in brains of EAE mice, as well as matched healthy normal controls, were quantified by collecting post-mortem high-resolution T2-weighted magnetic resonance microscopy and actively-stained magnetic resonance histology images. Anatomical delineations demonstrated a significant decrease in the volume of the whole cerebellum, cerebellar cortex, and molecular layer of the cerebellar cortex in EAE as compared to normal controls. The pro-apoptotic marker caspase-3 was detected in Purkinje cells and a significant decrease in Purkinje cell number was found in EAE. Cross modality and temporal correlations revealed a significant association between Purkinje cell loss on neuropathology and atrophy of the molecular layer of the cerebellar cortex by neuroimaging. These results demonstrate the power of using combined population atlasing and neuropathology approaches to discern novel insights underlying gray matter atrophy in animal models of neurodegenerative disease.
doi:10.1016/j.neuroimage.2009.06.073
PMCID: PMC2754586  PMID: 19589388
cerebellum; gray matter atrophy; mouse; MRI; multiple sclerosis
8.  Therapeutic testosterone administration preserves excitatory synaptic transmission in the hippocampus during autoimmune demyelinating disease 
Over 50% of multiple sclerosis (MS) patients experience cognitive deficits, and hippocampal-dependent memory impairment has been reported in over 30% of these patients. While post-mortem pathology studies and in vivo magnetic resonance imaging (MRI) demonstrate that the hippocampus is targeted in MS, the neuropathology underlying hippocampal dysfunction remains unknown. Furthermore, there are no treatments available to date to effectively prevent neurodegeneration and associated cognitive dysfunction in MS. We have recently demonstrated that the hippocampus is also targeted in experimental autoimmune encephalomyelitis (EAE), the most widely used animal model of MS. The objective of this study was to assess whether a candidate treatment (testosterone) could prevent hippocampal synaptic dysfunction and underlying pathology when administered in either a preventative or a therapeutic (post-disease induction) manner. Electrophysiological studies revealed impairments in basal excitatory synaptic transmission that involved both AMPA receptor-mediated changes in synaptic currents, and faster decay rates of NMDA receptor-mediated currents in mice with EAE. Neuropathology revealed atrophy of the pyramidal and dendritic layers of hippocampal cornu ammonis 1 (CA1), decreased pre (Synapsin-1) and post (postsynaptic density 95; PSD-95) synaptic staining, diffuse demyelination, and microglial activation. Testosterone treatment administered either before or after disease induction restores excitatory synaptic transmission as well as pre- and postsynaptic protein levels within the hippocampus. Furthermore, cross-modality correlations demonstrate that fluctuations in excitatory postsynaptic potentials are significantly correlated to changes in postsynaptic protein levels and suggest that PSD-95 is a neuropathological substrate to impaired synaptic transmission in the hippocampus during EAE. This is the first report demonstrating that testosterone is a viable therapeutic treatment option that can restore both hippocampal function and disease-associated pathology that occur during autoimmune disease.
doi:10.1523/JNEUROSCI.2796-12.2012
PMCID: PMC3571760  PMID: 22956822
hippocampus; synaptic transmission; testosterone; PSD-95; experimental autoimmune encephalomyelitis; Multiple Sclerosis
9.  Abnormal thalamocortical structural and functional connectivity in juvenile myoclonic epilepsy 
Brain  2012;135(12):3635-3644.
Juvenile myoclonic epilepsy is the most common idiopathic generalized epilepsy, characterized by frequent myoclonic jerks, generalized tonic-clonic seizures and, less commonly, absences. Neuropsychological and, less consistently, anatomical studies have indicated frontal lobe dysfunction in the disease. Given its presumed thalamo–cortical basis, we investigated thalamo–cortical structural connectivity, as measured by diffusion tensor imaging, in a cohort of 28 participants with juvenile myoclonic epilepsy and detected changes in an anterior thalamo–cortical bundle compared with healthy control subjects. We then investigated task-modulated functional connectivity from the anterior thalamic region identified using functional magnetic resonance imaging in a task consistently shown to be impaired in this group, phonemic verbal fluency. We demonstrate an alteration in task-modulated connectivity in a region of frontal cortex directly connected to the thalamus via the same anatomical bundle, and overlapping with the supplementary motor area. Further, we show that the degree of abnormal connectivity is related to disease severity in those with active seizures. By integrating methods examining structural and effective interregional connectivity, these results provide convincing evidence for abnormalities in a specific thalamo–cortical circuit, with reduced structural and task-induced functional connectivity, which may underlie the functional abnormalities in this idiopathic epilepsy.
doi:10.1093/brain/aws296
PMCID: PMC3525058  PMID: 23250883
juvenile myoclonic epilepsy; connectivity; functional MRI; diffusion MRI
10.  Increased d-amino acid oxidase expression in the bilateral hippocampal CA4 of schizophrenic patients: a post-mortem study 
Journal of Neural Transmission  2009;116(12):1657-1665.
An important risk gene in schizophrenia is d-amino acid oxidase (DAAO). To establish if expression of DAAO is altered in cortical, hippocampal or thalamic regions of schizophrenia patients, we measured gene expression of DAAO in a post-mortem study of elderly patients with schizophrenia and non-affected controls in both hemispheres differentiating between gray and white matter. We compared cerebral post-mortem samples (granular frontal cortex BA9, middle frontal cortex BA46, superior temporal cortex BA22, entorhinal cortex BA28, sensoric cortex BA1–3, hippocampus (CA4), mediodorsal nucleus of the thalamus) from 10 schizophrenia patients to 13 normal subjects investigating gene expression of DAAO in the gray and white matter of both hemispheres of the above-mentioned brain regions by in situ-hybridization. We found increased expression of DAAO-mRNA in the hippocampal CA4 of schizophrenic patients. Compared to the control group, both hemispheres of the hippocampus of schizophrenic patients showed an increased expression of 46% (right, P = 0.013) and 54% (left, P = 0.019), respectively. None of the other regions examined showed statistically significant differences in DAAO expression. This post-mortem study demonstrated increased gene expression of DAAO in the left and right hippocampus of schizophrenia patients. This increased expression could be responsible for a decrease in local d-serine levels leading to a NMDA-receptor hypofunction that is hypothesized to play a major role in the pathophysiology of schizophrenia. However, our study group was small and results should be verified using larger samples.
doi:10.1007/s00702-009-0312-z
PMCID: PMC2776935  PMID: 19823762
DAAO; Gene expression; Schizophrenia; In situ hybridization; Hippocampus
11.  Disease-specific molecular events in cortical multiple sclerosis lesions 
Brain  2013;136(6):1799-1815.
Cortical lesions constitute an important part of multiple sclerosis pathology. Although inflammation appears to play a role in their formation, the mechanisms leading to demyelination and neurodegeneration are poorly understood. We aimed to identify some of these mechanisms by combining gene expression studies with neuropathological analysis. In our study, we showed that the combination of inflammation, plaque-like primary demyelination and neurodegeneration in the cortex is specific for multiple sclerosis and is not seen in other chronic inflammatory diseases mediated by CD8-positive T cells (Rasmussen’s encephalitis), B cells (B cell lymphoma) or complex chronic inflammation (tuberculous meningitis, luetic meningitis or chronic purulent meningitis). In addition, we performed genome-wide microarray analysis comparing micro-dissected active cortical multiple sclerosis lesions with those of tuberculous meningitis (inflammatory control), Alzheimer’s disease (neurodegenerative control) and with cortices of age-matched controls. More than 80% of the identified multiple sclerosis-specific genes were related to T cell-mediated inflammation, microglia activation, oxidative injury, DNA damage and repair, remyelination and regenerative processes. Finally, we confirmed by immunohistochemistry that oxidative damage in cortical multiple sclerosis lesions is associated with oligodendrocyte and neuronal injury, the latter also affecting axons and dendrites. Our study provides new insights into the complex mechanisms of neurodegeneration and regeneration in the cortex of patients with multiple sclerosis.
doi:10.1093/brain/awt110
PMCID: PMC3673462  PMID: 23687122
multiple sclerosis; cortex; gene expression; demyelination; neurodegeneration
12.  Focal and Diffuse Cortical Degenerative Changes in a Marmoset Model of Multiple Sclerosis 
Background
Degenerative features such as neuronal, glial, synaptic and axonal loss have been identified in neocortical and other grey matter structures in patients with multiple sclerosis, but mechanisms for neurodegeneration are unclear. Cortical demyelinating lesions are a potential cause of this degeneration but the pathological and clinical significance of these lesions is uncertain, as they remain difficult to identify and study in vivo. In this study we aimed to describe and quantify cellular and subcellular pathology in the cortex of MOG-induced marmoset experimental autoimmune encephalomyelitis using quantitative immunohistochemical methods.
Results
We found evidence of diffuse axonal damage occurring throughout cortical grey matter with evidence for synaptic loss and gliosis and a 13.6% decrease in neuronal size and occurring in deep cortical layers. Evidence of additional axonal damage and a 29.6–36.5% loss of oligodendrocytes was found in demyelinated cortical lesions. Leucocortical lesions also showed neuronal loss of 22.2% and a 15.8% increase in oligodendrocyte size.
Conclusions
The marmoset EAE model therefore shows both focal and generalised neurodegeneration. The generalised changes cannot be directly related to focal lesions, suggesting that they either are a consequence of diffusible inflammatory factors or secondary to remote lesions acting through trans-synaptic or retrograde degeneration.
doi:10.1177/1352458509360362
PMCID: PMC2874633  PMID: 20194580
multiple sclerosis; cortex; inflammation; neurodegeneration; experimental autoimmune encephalomyelitis; marmoset; Callithrix jacchus; immunohistochemistry; demyelination; myelin oligodendrocyte glycoprotein
13.  Thalamo-striato-cortical determinants to fatigue in multiple sclerosis 
Brain and Behavior  2013;3(6):715-728.
Background
The aim was to explore the thalamo-striato-cortical theory of central fatigue in multiple sclerosis (MS) patients with self-reported fatigue. If the theory correctly predicted fatigue based on disruptions of the thalamo-striato-cortical network, we expected altered brain activation in this network in MS participants while performing a complex cognitive task that challenged fatigue.
Methods
MS participants with self-reported fatigue were examined by functional magnetic resonance imaging (fMRI) during the performance of a complex working memory task. In this task, cognitive effort was challenged by a parametric design, which modeled the cerebral responses at increasing cognitive demands. In order to explore the theory of central fatigue in MS we also analyzed the cerebral responses by adding perceived fatigue scores as covariates in the analysis and by calculating the functional connectivity between regions in the thalamo-striatocortical network. The main findings were that MS participants elicited altered brain responses in the thalamo-striato-cortical network, and that brain activation in the left posterior parietal cortex and the right substantia nigra was positively correlated to perceived fatigue ratings. MS participants had stronger cortical-to-cortical and subcortical-to-subcortical connections, whereas they had weaker cortical-to-subcortical connections.
Conclusions
The findings of the present study indicate that the thalamo-striato-cortical network is involved in the pathophysiology of fatigue in MS, and provide support for the theory of central fatigue. However, due to the limited number of participants and the somewhat heterogeneous sample of MS participants, these results have to be regarded as tentative, though they might serve as a basis for future studies.
doi:10.1002/brb3.181
PMCID: PMC3868176  PMID: 24363974
Basal ganglia; functional magnetic resonance imaging; parietal cortex; substantia nigra; working memory
14.  Mapping Cortical Degeneration in ALS with Magnetization Transfer Ratio and Voxel-Based Morphometry 
PLoS ONE  2013;8(7):e68279.
Pathological and imaging data indicate that amyotrophic lateral sclerosis (ALS) is a multisystem disease involving several cerebral cortical areas. Advanced quantitative magnetic resonance imaging (MRI) techniques enable to explore in vivo the volume and microstructure of the cerebral cortex in ALS. We studied with a combined voxel-based morphometry (VBM) and magnetization transfer (MT) imaging approach the capability of MRI to identify the cortical areas affected by neurodegeneration in ALS patients. Eighteen ALS patients and 18 age-matched healthy controls were examined on a 1.5T scanner using a high-resolution 3D T1 weighted spoiled gradient recalled sequence with and without MT saturation pulse. A voxel-based analysis (VBA) was adopted in order to automatically compute the regional atrophy and MT ratio (MTr) changes of the entire cerebral cortex. By using a multimodal image analysis MTr was adjusted for local gray matter (GM) atrophy to investigate if MTr changes can be independent of atrophy of the cerebral cortex. VBA revealed several clusters of combined GM atrophy and MTr decrease in motor-related areas and extra-motor frontotemporal cortex. The multimodal image analysis identified areas of isolated MTr decrease in premotor and extra-motor frontotemporal areas. VBM and MTr are capable to detect the distribution of neurodegenerative alterations in the cortical GM of ALS patients, supporting the hypothesis of a multi-systemic involvement in ALS. MT imaging changes exist beyond volume loss in frontotemporal cortices.
doi:10.1371/journal.pone.0068279
PMCID: PMC3706610  PMID: 23874570
15.  Baló’s concentric sclerosis: imaging findings and pathological correlation 
Baló’s concentric sclerosis is a primary inflammatory central nervous system demyelinating disease that is considered a rare, radiographically and pathologically distinct variant of multiple sclerosis. Baló’s concentric sclerosis is characterized by alternating rings of demyelinated and myelinated axons, and it is most frequently diagnosed postmortem by autopsy or, more recently, by magnetic resonance imaging without pathologic verification. This report is of a case of Baló’s concentric sclerosis in which the patient presented with left-sided focal sensorimotor deficits. The patient’s lesion demonstrated characteristics of Baló’s concentric sclerosis by magnetic resonance imaging, but since a neoplastic process was also suspected initially, the patient underwent a surgical biopsy. This pathology sample now provides the opportunity to correlate the tissue diagnosis of demyelination with characteristic magnetic resonance imaging findings; this comparison is infrequently found in the literature.
doi:10.3941/jrcr.v7i6.1251
PMCID: PMC3888114  PMID: 24421937
Baló’s concentric sclerosis; demyelinating disease; MRI; Pathology
16.  Dynamic changes in cerebello-thalamo-cortical motor circuitry during progression of Parkinson’s disease 
Neuroscience  2009;166(2):712-719.
Both the basal ganglia and cerebellum are known to influence cortical motor and motor-associated areas via the thalamus. Whereas striato-thalamo-cortical (STC) motor circuit dysfunction has been implicated clearly in Parkinson’s disease (PD), the role of the cerebello-thalamo-cortical (CTC) motor circuit has not been well defined. Functional magnetic resonance imaging (fMRI) is a convenient tool for studying the role of the CTC in vivo in PD patients, but large inter-individual differences in fMRI activation patterns require very large numbers of subjects in order to interpret data from cross-sectional, case control studies. To understand the role of the CTC during PD progression, we obtained longitudinal fMRI two years apart from five PD (57 ± 8 yr) and five Controls (57 ± 9 yr) performing either externally- (EG) or internally-guided (IG) sequential finger movements. All PD subjects had unilateral motor symptoms at baseline, but developed bilateral symptoms at follow-up. Within-group analyses were performed by comparing fMRI activation patterns between baseline and follow-up scans. Between-group comparisons were made by contrasting fMRI activation patterns generated by the more-affected and less-affected hands of PD subjects with the dominant and non-dominant hands of Controls, respectively. Compared to baseline, Controls showed changes in CTC circuits, but PD subjects had increased recruitment of both cortical motor-associated and cerebellar areas. Compared to Controls, PD subjects demonstrated augmented recruitment of CTC circuits over time that was statistically significant when the IG task was performed by the hand that transitioned from non-symptomatic to symptomatic. This longitudinal fMRI study demonstrates increased recruitment of the CTC motor circuit concomitant with PD progression, suggesting a role of the CTC circuit in accommodation to, or pathophysiology of, PD.
doi:10.1016/j.neuroscience.2009.12.036
PMCID: PMC2852615  PMID: 20034546
Parkinson’s disease; Longitudinal; FMRI; Cerebellum; Neurocircuits; Motor Control
17.  DTI detects water diffusion abnormalities in the thalamus that correlate with an extremity pain episode in a patient with multiple sclerosis☆ 
NeuroImage : Clinical  2013;2:258-262.
Background
Various types of multiple sclerosis (MS) related pain have been discussed. One concept is that deafferentation secondary to lesions in the spino-thalamo-cortical network can cause central pain. However, this hypothesis is somehow limited by a lack of a robust association between pain episodes and sites of lesion location.
Objective
We tested the hypothesis that temporary tissue alterations in the thalamus that are not detectable by conventional magnetic resonance imaging (T1w, FLAIR) can potentially explain a focal, paroxysmal central pain episode of a patient with MS. For microstructural tissue assessment we employed ten longitudinal diffusion tensor imaging (DTI) examinations.
Results
We could demonstrate an abnormal, unilateral temporary increase of the fractional anisotropy (FA) in the thalamus contralateral to the affected body side. Before the pain episode and after pain relief the FA reached completely normal values as seen in identically investigated age and gender matched 100 healthy control subjects.
Conclusion
These findings suggest that: i.) frequently applied and quantitatively evaluated DTI could be used as a sensitive imaging technique for detection of pathological processes associated with MS not detectable with conventional imaging strategies, ii.) temporary pathological processes in the “normal-appearing” thalamus may explain waxing and waning symptoms like episodes of central pain, and iii.) cross-sectional case examinations on (MS) patients with central pain should be performed to investigate how often thalamic alterations occur together with central pain.
Highlights
► Illustration of robustness of quantitative assessment of thalamus microstructure by DTI ► “Normal-appearing” thalamus may explain central pain in multiple sclerosis. ► Suggestion of deep gray matter assessment by DTI in multiple sclerosis
doi:10.1016/j.nicl.2013.01.008
PMCID: PMC3778262  PMID: 24179780
18.  Inflammatory Cortical Demyelination in Early Multiple Sclerosis 
The New England Journal of Medicine  2011;365(23):2188-2197.
BACKGROUND
Cortical disease has emerged as a critical aspect of the pathogenesis of multiple sclerosis, being associated with disease progression and cognitive impairment. Most studies of cortical lesions have focused on autopsy findings in patients with long-standing, chronic, progressive multiple sclerosis, and the noninflammatory nature of these lesions has been emphasized. Magnetic resonance imaging studies indicate that cortical damage occurs early in the disease.
METHODS
We evaluated the prevalence and character of demyelinating cortical lesions in patients with multiple sclerosis. Cortical tissues were obtained in passing during biopsy sampling of white-matter lesions. In most cases, biopsy was done with the use of stereotactic procedures to diagnose suspected tumors. Patients with sufficient cortex (138 of 563 patients screened) were evaluated for cortical demyelination. Using immunohistochemistry, we characterized cortical lesions with respect to demyelinating activity, inflammatory infiltrates, the presence of meningeal inflammation, and a topographic association between cortical demyelination and meningeal inflammation. Diagnoses were ascertained in a subgroup of 77 patients (56%) at the last follow-up visit (at a median of 3.5 years).
RESULTS
Cortical demyelination was present in 53 patients (38%) (104 lesions and 222 tissue blocks) and was absent in 85 patients (121 tissue blocks). Twenty-five patients with cortical demyelination had definite multiple sclerosis (81% of 31 patients who underwent long-term follow-up), as did 33 patients without cortical demyelination (72% of 46 patients who underwent long-term follow-up). In representative tissues, 58 of 71 lesions (82%) showed CD3+ T-cell infiltrates, and 32 of 78 lesions (41%) showed macrophage-associated demyelination. Meningeal inflammation was topographically associated with cortical demyelination in patients who had sufficient meningeal tissue for study.
CONCLUSIONS
In this cohort of patients with early-stage multiple sclerosis, cortical demyelinating lesions were frequent, inflammatory, and strongly associated with meningeal inflammation. (Funded by the National Multiple Sclerosis Society and the National Institutes of Health.)
doi:10.1056/NEJMoa1100648
PMCID: PMC3282172  PMID: 22150037
19.  Genetic influences in emotional dysfunction and alcoholism-related brain damage 
Alcoholism is a complex, multifactorial disorder involving problematic ethanol ingestion; it results from the interplay between genetic and environmental factors. Personality, likewise, is formed from a combination of inherited and acquired influences. Because selected dimensions of emotional temperament are associated with distinct neurochemical substrates contributing to specific personality phenotypes, certain aspects of abnormal emotional traits in alcoholics may be inherited. Emotions involve complex subjective experiences engaging multiple brain regions, most notably the cortex, limbic system, and cerebellum. Results of in vivo magnetic resonance imaging and post-mortem neuropathological studies of alcoholics indicate that the greatest cortical loss occurs in the frontal lobes, with concurrent thinning of the corpus callosum. Additional damage has been documented for the amygdala and hippocampus, as well as in the white matter of the cerebellum. All of the critical areas of alcoholism-related brain damage are important for normal emotional functioning. When changes occur in these brain regions, either as a consequence of chronic ethanol abuse or from a genetic anomaly affecting temperament and/or a vulnerability to alcoholism, corresponding changes in emotional functions are to be expected. In alcoholics, such changes have been observed in their perception and evaluation of emotional facial expressions, interpretation of emotional intonations in vocal utterances, and appreciation of the meaning of emotional materials.
PMCID: PMC2416753  PMID: 18568071
alcoholism; personality; emotional dysfunction; genetic influences
20.  Low-Frequency BOLD Fluctuations Demonstrate Altered Thalamocortical Connectivity in Schizophrenia 
Schizophrenia Bulletin  2008;36(4):713-722.
The thalamus plays a central and dynamic role in information transmission and processing in the brain. Multiple studies reveal increasing association between schizophrenia and dysfunction of the thalamus, in particular the medial dorsal nucleus (MDN), and its projection targets. The medial dorsal thalamic connections to the prefrontal cortex are of particular interest, and explicit in vivo evidence of this connection in healthy humans is sparse. Additionally, recent neuroimaging evidence has demonstrated disconnection among a variety of cortical regions in schizophrenia, though the MDN thalamic prefrontal cortex network has not been extensively probed in schizophrenia. To this end, we have examined thalamo-anterior cingulate cortex connectivity using detection of low-frequency blood oxygen level dependence fluctuations (LFBF) during a resting-state paradigm. Eleven schizophrenic patients and 12 healthy control participants were enrolled in a study of brain thalamocortical connectivity. Resting-state data were collected, and seed-based connectivity analysis was performed to identify the thalamocortical network. First, we have shown there is MDN thalamocortical connectivity in healthy controls, thus demonstrating that LFBF analysis is a manner to probe the thalamocortical network. Additionally, we have found there is statistically significantly reduced thalamocortical connectivity in schizophrenics compared with matched healthy controls. We did not observe any significant difference in motor networks between groups. We have shown that the thalamocortical network is observable using resting-state connectivity in healthy controls and that this network is altered in schizophrenia. These data support a disruption model of the thalamocortical network and are consistent with a disconnection hypothesis of schizophrenia.
doi:10.1093/schbul/sbn145
PMCID: PMC2894601  PMID: 18990709
schizophrenia; thalamus; connectivity; fcMRI; resting state; cingulate
21.  Distinct Thalamo-Cortical Controls for Shoulder, Elbow, and Wrist during Locomotion 
Recent data from this laboratory on differential controls for the shoulder, elbow, and wrist exerted by the thalamo-cortical network during locomotion is presented, based on experiments involving chronically instrumented cats walking on a flat surface and along a horizontal ladder. The activity of the following three groups of neurons is characterized: (1) neurons of the motor cortex that project to the pyramidal tract (PTNs), (2) neurons of the ventrolateral thalamus (VL), many identified as projecting to the motor cortex (thalamo-cortical neurons, TCs), and (3) neurons of the reticular nucleus of thalamus (RE), which inhibit TCs. Neurons were grouped according to their receptive field into shoulder-, elbow-, and wrist/paw-related categories. During simple locomotion, shoulder-related PTNs were most active in the late stance and early swing, and on the ladder, often increased activity and stride-related modulation while reducing discharge duration. Elbow-related PTNs were most active during late swing/early stance and typically remained similar on the ladder. Wrist-related PTNs were most active during swing, and on the ladder often decreased activity and increased modulation while reducing discharge duration. In the VL, shoulder-related neurons were more active during the transition from swing-to-stance. Elbow-related cells tended to be more active during the transition from stance-to-swing and on the ladder often decreased their activity and increased modulation. Wrist-related neurons were more active throughout the stance phase. In the RE, shoulder-related cells had low discharge rates and depths of modulation and long periods of activity distributed evenly across the cycle. In sharp contrast, wrist/paw-related cells discharged synchronously during the end of stance and swing with short periods of high activity, high modulation, and frequent sleep-type bursting. We conclude that thalamo-cortical network processes information related to different segments of the forelimb differently and exerts distinct controls over the shoulder, elbow, and wrist during locomotion.
doi:10.3389/fncom.2013.00062
PMCID: PMC3659318  PMID: 23734124
cat; motor cortex; thalamus; PTN; ventro-lateral thalamus; reticular nucleus of thalamus; accuracy; walking
22.  Quantitative Magnetic Resonance of Post Mortem Multiple Sclerosis Brain before and after Fixation 
Unfixed and fixed post mortem multiple sclerosis (MS) brain is being used to probe pathology underlying quantitative MR (qMR) changes. Effects of fixation on qMR indices in MS brain are unknown. In 15 post mortem MS brain slices T1, T2, MT ratio (MTR), macromolecular proton fraction (fB), mean, axial and radial diffusivity (MD, Dax and Drad), and fractional anisotropy (FA) were assessed in white matter (WM) lesions (WML) and normal appearing WM (NAWM) before and after fixation in formalin. Myelin content, axonal count and gliosis were quantified histologically. Student's t-test and regression were used for analysis. T1, T2, MTR, and fB obtained in unfixed MS brain were similar to published values obtained in patients with MS in vivo. Following fixation T1, T2 (NAWM, WML) and MTR (NAWM) dropped, whereas fB (NAWM, WML) increased. Compared to published in vivo data all diffusivity measures were lower in unfixed MS brain, and dropped further following fixation (except for FA). MTR was the best predictor of myelin in unfixed MS brain (r=−0.83; p<0.01) whereas post-fixation T2 (r=0.92; p<0.01), T1 (r=−0.89; p<0.01) and fB (r=−0.86; p<0.01) were superior. All diffusivity measures (except for Dax in unfixed tissue) were predictors of myelin content.
doi:10.1002/mrm.21487
PMCID: PMC2241759  PMID: 18228601
23.  Mechanisms of deep brain stimulation for obsessive compulsive disorder: effects upon cells and circuits 
Deep brain stimulation (DBS) has emerged as a safe, effective, and reversible treatment for a number of movement disorders. This has prompted investigation of its use for other applications including psychiatric disorders. In recent years, DBS has been introduced for the treatment of obsessive compulsive disorder (OCD), which is characterized by recurrent unwanted thoughts or ideas (obsessions) and repetitive behaviors or mental acts performed in order to relieve these obsessions (compulsions). Abnormal activity in cortico-striato-thalamo-cortical (CSTC) circuits including the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), ventral striatum, and mediodorsal (MD) thalamus has been implicated in OCD. To this end a number of DBS targets including the anterior limb of the internal capsule (ALIC), ventral capsule/ventral striatum (VC/VS), ventral caudate nucleus, subthalamic nucleus (STN), and nucleus accumbens (NAc) have been investigated for the treatment of OCD. Despite its efficacy and widespread use in movement disorders, the mechanism of DBS is not fully understood, especially as it relates to psychiatric disorders. While initially thought to create a functional lesion akin to ablative procedures, it is increasingly clear that DBS may induce clinical benefit through activation of axonal fibers spanning the CSTC circuits, alteration of oscillatory activity within this network, and/or release of critical neurotransmitters. In this article we review how the use of DBS for OCD informs our understanding of both the mechanisms of DBS and the circuitry of OCD. We review the literature on DBS for OCD and discuss potential mechanisms of action at the neuronal level as well as the broader circuit level.
doi:10.3389/fnint.2012.00029
PMCID: PMC3375018  PMID: 22712007
deep brain stimulation; obsessive compulsive disorder; neuromodulation; cortico-striato-thalamocortical circuit
24.  Regional changes in thalamic shape and volume with increasing age 
Neuroimage  2012;63(3):1134-1142.
The thalamus undergoes significant volume loss and microstructural change with increasing age. Alterations in thalamo-cortical connectivity may contribute to the decline in cognitive ability associated with aging. The aim of this study was to assess changes in thalamic shape and in the volume and diffusivity of thalamic regions parcellated by their connectivity to specific cortical regions in order to test the hypothesis age related thalamic change primarily affects thalamic nuclei connecting to the frontal cortex.
Using structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI), we assessed thalamic volume and diffusivity in 86 healthy volunteers, median (range) age 44 (20–74) years. Regional thalamic micro and macro structural changes were assessed by segmenting the thalamus based on connectivity to the frontal, parietal, temporal and occipital cortices and determining the volumes and mean diffusivity of the thalamic projections.
Linear regression analysis was performed to test the relationship between increasing age and (i) normalised thalamic volume, (ii) whole thalamus diffusion measures, (iii) mean diffusivity (MD) of the thalamo-cortical projections, and (iv) volumes of the thalamo-cortical projections. We also assessed thalamic shape change using vertex analysis.
We observed a significant reduction in the volume and a significant increase in MD of the whole thalamus with increasing age. The volume of the thalamo-frontal projections decreased significantly with increasing age, however there was no significant relationship between the volumes of the thalamo-cortical projections to the parietal, temporal, and occipital cortex and age. Thalamic shape analysis showed that the greatest shape change was in the anterior thalamus, incorporating regions containing the anterior nucleus, the ventroanterior nucleus and the dorsomedial nucleus. To explore these results further we studied two additional groups of subjects (a younger and an older aged group, n = 20), which showed that the volume of the thalamo-frontal projections was correlated to executive functions scores, as assessed by the Stroop test. These data suggest that atrophy of the frontal thalamo-cortical unit may explain, at least in part, disorders of attention, working memory and executive function associated with increasing age.
doi:10.1016/j.neuroimage.2012.07.043
PMCID: PMC3507623  PMID: 22846656
Healthy aging; Thalamus; Thalamo-cortical connectivity; Diffusion tensor imaging; Vertex analysis
25.  Schizophrenia and Sex Associated Differences in the Expression of Neuronal and Oligodendrocyte Specific Genes in Individual Thalamic Nuclei 
Schizophrenia research  2007;98(1-3):118-128.
Considerable evidence based on the study of post-mortem brain tissue suggests deficits in both neuronal and myelin systems in schizophrenia (SZ). To date, most (may be “the majority of the”?) biochemical and molecular biological studies have focused on the cerebral cortex. Most information traveling to or from the cortex is relayed or synaptically gated through the thalamus, and numerous studies suggest structural and functional abnormalities in interconnected regions of the thalamus and cortex in SZ. The present study extends our gene expression studies of neuronal and myelin systems to the thalamus. Quantitative PCR was employed to assess the expression of 10 genes in 5 divisions of the thalamus which were precisely harvested using laser capture microdissection. The divisions studies were present on coronal sections at the level of the centromedian nucleus (CMN) taken from 14 schizophrenic and 16 normal control postmortem brains. The genes examined were specific for oligodendrocytes (MAG, CNP, MBP), neurons (ENO2), glutamatergic neurons (VGlut1, VGlut-2, PV, CB) or GABAergic neurons (GAD65, GAD67). Expression levels for each of these markers were quantitated and compared between diagnoses, between sexes, and across nuclei. CB was much more highly expressed in the CMN in SZs compared to NCs. No other diagnosis related differences in gene expression were observed. The expression levels of CNP and MAG, but not MBP, were highly correlated with one another and both, but not MBP, were much more highly expressed in females than in males in all thalamic divisions examined. All markers were differentially expressed across nuclei.
doi:10.1016/j.schres.2007.09.034
PMCID: PMC2678297  PMID: 18029146
Schizophrenia; Thalamus; Neurons; Oligodendrocytes; Gene Expression

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