Basal Ganglia Regions Research Articles

Neurocognitive profile analysis in obsessive-compulsive disorder

Although neurocognitive deficits have been identified in obsessive-compulsive disorder (OCD), little research has focused on whether these deficits are generalized or specific to a given cognitive domain. We assessed the relative strengths and weaknesses of 26 adult patients with OCD compared to 38 age- and sex-matched healthy volunteers in domains of motor, verbal memory, visual memory, reasoning/problem solving, processing speed processing, and language. Profile analysis revealed an overall neurocognitive deficit of 1/2 standard deviation in OCD patients versus healthy volunteers, with relative weaknesses in motor and processing speed domains. In contrast, relative strengths were observed in language, verbal memory, and reasoning/problem solving. Our findings demonstrate neurocognitive impairment in OCD that may relate to functional outcome in this population. Findings of specific abnormalities on tasks of motor and processing speed are consistent with a hypothesized role of thalamocortical and basal ganglia regions in the pathogenesis of OCD.

A rhesus monkey reference label atlas for template driven segmentation

We have acquired dual-echo spin-echo (DE SE) MRI data of the rhesus monkey brain since 1994 as part of an ongoing study of normal aging. To analyze these legacy data for regional volume changes, we have created a reference label atlas for the Template Driven Segmentation (TDS) algorithm. The atlas was manually created from DE SE legacy MRI data of one behaviorally normal, young, male rhesus monkey and consisted of 14 regions of interest (ROI's). We analyzed the reproducibility and validity of the TDS algorithm using the atlas relative to manual segmentation. ROI volumes were comparable between the two segmentation methodologies, except TDS overestimated the volume of basal ganglia regions. Both methodologies were highly reproducible, but TDS had lower sensitivity and comparable specificity. TDS segmentation calculates accurate volumes for most ROI's. Sensitivity will be improved in future studies through the acquisition of higher quality data.

30 year old woman with possible Creutzfeldt-Jakob Disease initially presenting with psychiatric symptoms: a case report

Results The patient's problems had begun six months prior to hospital admission with symptoms of disorientation in place and time and behavioral disturbances. She was treated initially as a psychiatric outpatient receiving medication. After 4 months of unsuccessful treatment she was hospitalized and subjected to 16 E.C.T. sessions. About 2 months after E.C.T., the patient was admitted to our hospital with neurological symtomatology (gait and speech disturbances). Biochemical examination, E.E.G and lumbar puncture (including protein 14-3-3 assay) were inconclusive, while brain MRI revealed brain atrophy and high signal intensity in the region of basal ganglia, imaging suggestive of Creutzfeldt-Jakob Disease. 22 months after initial presentation the patient is in a state of akinetic mutism. Conclusions To our knowledge this is the first report presenting in Greece concerning possible Creutzfeldt-Jakob Disease in such a young person. The initial presentation with pure psychiatric symptoms is also of interest, while the time elapsed since the presentation of neurological symtomatology is considered to be quite long.

Regionally selective changes in neurotransmitter receptors in the brain of the 5-HT 1B knockout mouse

The serotonin 1B receptor knockout (5-HT 1B KO) mouse is a valuable animal model of addiction to psychostimulants. We previously found selective increases in dopamine (DA) turnover in the nucleus accumbens of these mice, in addition to several changes in their central serotonin system. Here, we searched for further DA adaptations by measuring D 1 and D 2 receptor as well DA plasma membrane transporter (DAT) sites by ligand binding autoradiography, and G-protein coupling to D 1 and D 2 receptors by [ 35S]GTPγS autoradiography. Except for a slight increase in the lateral septum, D 1 receptor binding did not differ from wild-type in twenty-one other neocortical, limbic or basal ganglia regions examined in the KO. Nor were there changes in D 1 agonist-stimulated G-protein coupling in any of these regions, including the lateral septum. Increases in D 2 binding sites, presumably involving GABAergic projection neurons, were measured in the nucleus accumbens, olfactory tubercle and ventral tegmental area of the 5-HT 1B KO. However, no activation of the efficacy of D 2 receptor coupling to G-protein could be measured in these and other brain regions. Binding to DAT was unchanged throughout brain. Because of their implication in cocaine addiction, the functionality of μ-opioid and GABA B receptors was also assessed by [ 35S]GTPγS autoradiography. 5-HT 1B KO showed selective decreases in G-protein coupling to μ-opioid receptors in the paraventricular thalamic nucleus, and to GABA B receptors in the basolateral nucleus of amygdala. It is likely that these latter changes underlie some aspects of the addictive behavior of the 5-HT 1B KO mouse.

LANGUAGE AND PARKINSON'S DISEASE

Parkinson's disease, the most common progressive neurological movement disorder worldwide, causes slow deterioration of subcortical structures and dopamine deficiency, and the disruption of circuits connecting frontal lobe and basal ganglia regions. Although the motor and cognitive consequences of these structural and physiological changes have been well-documented, only a limited, albeit growing, empirical literature has examined the integrity of language abilities in individuals with Parkinson's disease. This article reviews recent advances in that literature that have furthered our understanding of the quantitative and qualitative changes in morphosyntactic, lexical-semantic, and discourse levels of language functioning associated with Parkinson's disease. This article also discusses the theoretical and applied implications of these linguistic symptoms and provides suggestions to forward this line of research.

Dihydrotetrabenazine positron emission tomography imaging in early, untreated Parkinson's disease

To determine the sensitivity of positron emission tomography with 11C-labeled dihydrotetrabenazine (DTBZ) to the nigrostriatal changes associated with early, untreated Parkinson's disease (PD), and to determine the correlation between any regionally reduced DTBZ binding and the major motor features of PD. Untreated patients with early PD (n = 27) and age-matched control subjects (n = 33) underwent DTBZ/positron emission tomography scanning to measure binding to the presynaptic type 2 vesicular monoamine transporter site in dopaminergic neurons in basal ganglia regions. Clinical symptoms were rated with the Unified Parkinson's Disease Rating Scale. Mean striatal DTBZ binding values in the patient group were decreased as compared with control subjects (p < 0.001) in all regions examined. The difference between patients and control subjects was most marked in the midputamen, where only one patient had DTBZ binding within 3 standard deviations of the control mean. Bradykinesia and rigidity scores correlated with DTBZ binding in the contralateral midputamen region, particularly for the clinically least affected limbs. Tremor scores showed no significant correlation. Reduced striatal binding of DTBZ is associated with early PD. Tremor appears to be only partially related to presynaptic dopaminergic function and may have a mechanism differing from that of symptoms such as bradykinesia. The method appears to be most sensitive in mildly affected individuals with a possible "floor" effect that may limit the degree of additional change occurring once more severe clinical symptoms are evident.

Effects of Visual and Auditory Feedback on Sensorimotor Circuits in the Basal Ganglia

Previous work using visual feedback has identified two distinct sensorimotor circuits in the basal ganglia (BG): one that scaled with the duration of force and one that scaled with the rate of change of force. The present study compared functional MRI signal changes in the BG during a grip force task using either visual or auditory feedback to determine whether the BG nuclei process auditory and visual feedback similarly. We confirmed the same two sensorimotor circuits in the BG. Activation in the striatum and external globus pallidus (GPe) scaled linearly with the duration of force under visual and auditory feedback conditions, with similar slopes and intercepts across feedback type. The pattern of signal change for the internal globus pallidus (GPi) and subthalamic nucleus (STN) was nonlinear and parameters of the exponential function were altered by feedback type. Specifically, GPi and STN activation decreased exponentially with the rate of change of force. The rate constant and asymptote of the exponential functions for GPi and STN were greater during auditory than visual feedback. In a comparison of the BOLD signal between BG regions, GPe had the highest percentage of variance accounted for and this effect was preserved for both feedback types. These new findings suggest that neuronal activity of specific BG nuclei is affected by whether the feedback is derived from visual or auditory inputs. Also, the data are consistent with the hypothesis that the GPe has a high level of information convergence from other BG nuclei, which is preserved across different sensory feedback modalities.

Cerebral microbleeds in the population based AGES-Reykjavik study: prevalence and location

Background and purpose: Incidental foci of signal loss suggestive of cerebral microbleeds (CMBs) are frequent findings on gradient echo T2* weighted MRI (T2* MRI) of patients with haemorrhagic or ischaemic...

Midbrain iron content in early Parkinson disease

Parkinson disease (PD) is a progressive neurodegenerative disorder in which the major pathologic substrate is a loss of dopaminergic neurons from the lateral substantia nigra pars compacta (SNc). Our objective was to determine whether, in patients with early PD, SNc changes evident on MRI sequences sensitive to iron content corresponded anatomically to the pathologic changes reported previously, and to correlate these changes to the duration and severity of clinical manifestations of PD. Twenty-six untreated patients with early PD and 13 age- and gender-matched control subjects had MRI with a 3 tesla magnet using a multiple gradient echo sequence designed for rapid single-scan mapping of the proton transverse relaxation rate (R(2)*). R(2)* was calculated for midbrain and forebrain basal ganglia regions. Clinical features were rated with the Unified Parkinson's Disease Rating Scale. A difference in measured R(2)* values between patients and controls was observed in the lateral SNc (p <or= 0.005). Linear regression indicated a correlation between the lateralized motor score from the clinically most affected side and R(2)* values from the opposite lateral SNc (p = 0.01). High field strength MRI demonstrates lateral substantia nigra pars compacta abnormalities in early Parkinson disease (PD) consistent with increased iron content and corresponding to the known distribution of neuronal loss occurring in this disorder. This may ultimately provide an imaging marker for disease progression in PD, although longitudinal studies are required.

Compromised fronto-striatal functioning in HIV: An fMRI investigation of semantic event sequencing

The human immunodeficiency virus (HIV) damages fronto-striatal regions, and is associated with deficits in executive functioning. We recently developed a semantic event sequencing task based on the Picture Arrangement subtest of the Wechsler Adult Intelligence Scale-III for use with functional magnetic resonance imaging (fMRI) and found recruitment of dorsolateral prefrontal cortex and basal ganglia in healthy participants. To assess the impact of HIV on the functioning of the basal ganglia and prefrontal cortex, we administered this task to 11 HIV+ and 11 Control participants matched for age and education. Neuropsychological evaluation demonstrated that the HIV+ group had mild impairment in memory retrieval and motor functioning, but was not demented. Morphometric measurements suggested no atrophy in basal ganglia regions. The results of the fMRI analysis revealed hypoactivation of the left caudate, left dorsolateral prefrontal cortex, and bilateral ventral prefrontal cortex in the HIV+ group. Functional connectivity analysis demonstrated less functional connectivity between the caudate and prefrontal cortex and basal ganglia regions in the HIV+ group. In contrast, the HIV+ group demonstrated increased activation of right postcentral/supramarginal gyrus, and greater connectivity between the caudate and this same anterior parietal region. The results of this study extend previous investigations by demonstrating compromised function of the caudate and connected prefrontal regions in HIV during cognition. This disruption of fronto-striatal circuitry likely precedes the development of cognitive impairment in HIV.

Identification of the Transcriptional Targets of FOXP2, a Gene Linked to Speech and Language, in Developing Human Brain

Mutations in FOXP2, a member of the forkhead family of transcription factor genes, are the only known cause of developmental speech and language disorders in humans. To date, there are no known targets of human FOXP2 in the nervous system. The identification of FOXP2 targets in the developing human brain, therefore, provides a unique tool with which to explore the development of human language and speech. Here, we define FOXP2 targets in human basal ganglia (BG) and inferior frontal cortex (IFC) by use of chromatin immunoprecipitation followed by microarray analysis (ChIP-chip) and validate the functional regulation of targets in vitro. ChIP-chip identified 285 FOXP2 targets in fetal human brain; statistically significant overlap of targets in BG and IFC indicates a core set of 34 transcriptional targets of FOXP2. We identified targets specific to IFC or BG that were not observed in lung, suggesting important regional and tissue differences in FOXP2 activity. Many target genes are known to play critical roles in specific aspects of central nervous system patterning or development, such as neurite outgrowth, as well as plasticity. Subsets of the FOXP2 transcriptional targets are either under positive selection in humans or differentially expressed between human and chimpanzee brain. This is the first ChIP-chip study to use human brain tissue, making the FOXP2-target genes identified in these studies important to understanding the pathways regulating speech and language in the developing human brain. These data provide the first insight into the functional network of genes directly regulated by FOXP2 in human brain and by evolutionary comparisons, highlighting genes likely to be involved in the development of human higher-order cognitive processes.

Progressive Nonfluent Aphasia and Its Characteristic Motor Speech Deficits

Progressive nonfluent aphasia (PNFA) is a clinical syndrome characterized by motor speech impairment and agrammatism, with relative sparing of single word comprehension and semantic memory. PNFA has been associated with the characteristic pattern of left anterior insular and posterior frontal atrophy, including the motor and premotor regions and Broca's area. Postmortem histopathologic evidence has shown that PNFA is usually associated with tau pathology, although focal Alzheimer disease pathology and tau-negative, ubiquitin-TDP-43 inclusions also have been reported in association with this clinical syndrome. We performed a detailed analysis of motor speech errors in 18 patients with PNFA and investigated their neural correlates using voxel-based morphometry on magnetic resonance imaging scans. Seven patients demonstrated only apraxia of speech (AOS) errors, whereas 11 showed AOS along with dysarthria. Slow rate of speech, effortful articulation with groping, and consonant distortions were the most common AOS errors. Hypernasality was the most represented dysarthric feature and dysarthria was most often classified as spastic, hypokinetic, or mixed spastic-hypokinetic. Neuroimaging results demonstrated that patients with AOS-only and AOS plus dysarthria showed atrophy in the left posterior frontal, anterior insular, and basal ganglia regions when compared with controls. Patients with AOS plus dysarthria showed greater damage than patients with AOS-only in the left face portion of primary motor cortex and left caudate. PNFA is a distinct frontotemporal lobar degeneration clinical syndrome associated with characteristic clinical, neuroimaging, and pathologic features. The clinical features are driven by the severity of left frontal and caudate damage.

Region of interest template for the human basal ganglia: Comparing EPI and standardized space approaches

Identifying task-related activation in the basal ganglia (BG) is an important area of interest in normal motor systems and cognitive neuroscience. The purpose of this study was to compare changes in brain activation in the BG using results obtained from two different masking methods: a mask drawn in standardized space from a T1-weighted anatomical image and individual region of interest (ROI) masks drawn from each subject’s echo-planar image (EPI) from different tasks with reference to the high resolution fast spin echo image of each subject. Two standardized masks were used: a mask developed in Talairach space (Basal Ganglia Human Area Template (BGHAT)) and a mask developed in Montreal Neurological Institute space (MNI mask). Ten subjects produced fingertip force pulses in five separate contraction tasks during fMRI scanning. ROIs were the left caudate, putamen, external and internal portions of the globus pallidus, and subthalamic nucleus. ANOVA revealed a similar average number of voxels in the EPI mask across tasks in each BG region. The percent signal change (PSC) was consistent within each region regardless of which mask was used. Linear regression analyses between PSC in BGHAT and EPI masks and MNI and EPI masks yielded r2 values between 0.74–0.99 and 0.70–0.99 across regions, respectively. In conclusion, PSC in different BG ROIs can be compared across studies using these different masking methods. The masking method used does not affect the overall interpretation of results with respect to the effect of task. Use of a mask drawn in standardized space is a valid and time saving method of identifying PSC in the small nuclei of the BG.

Iron-induced experimental cortical seizures: Electroencephalographic mapping of seizure spread in the subcortical brain areas

The iron-induced model of post-traumatic chronic focal epilepsy in rats was studied by depth-electrode mapping to investigate the spread of epileptiform activity into subcortical brain structures after its onset in the cortical epileptic focus. Electrical seizure activity was recorded in the hippocampal CA1 and CA3 areas, amygdala and caudate-putamen, in rats with iron-induced chronic cortical focal epilepsy. These experiments showed that the epileptiform activity with its onset in the cortical focus synchronously propagated into the studied subcortical brain areas. Seizure behaviours seemed to increase in correspondence with the spread of the epileptic electrographic activity in subcortical areas. Comparison of the cortical focus electroencephalographic and associated multiple-unit action potential recordings with those from the subcortical structures showed that the occurrence and evolution of the epileptiform activity in the subcortical structures were in parallel with that in the cortical focus. The intracerebral anatomic progression and delineation of seizure spread (mapped by field potential (EEG) and multiple-unit action potentials (MUA) recordings) indicated participation of these regions in the generalization of seizure activity in this model of epilepsy. The seizure-induced activation of the hippocampus appeared to evolve into an epileptic focus independent of the cortical focus. The present study demonstrates the propagation of epileptic activity from the cortical focus into the limbic and basal ganglia regions. Treatment of iron-induced epileptic rats with ethosuximide, an anti-absence drug, resulted in suppression of the epileptiform activity in the cortical focus as well as in the subcortical brain areas.

In vivo imaging of disturbed pre- and post-synaptic dopaminergic signaling via arachidonic acid in a rat model of Parkinson's disease

Background Parkinson's disease involves loss of dopamine (DA)-producing neurons in the substantia nigra, associated with fewer pre-synaptic DA transporters (DATs) but more post-synaptic dopaminergic D 2 receptors in terminal areas of these neurons. Hypothesis Arachidonic acid (AA) signaling via post-synaptic D 2 receptors coupled to cytosolic phospholipase A 2 (cPLA 2) will be reduced in terminal areas ipsilateral to a chronic unilateral substantia nigra lesion in rats given d-amphetamine, which reverses the direction of the DAT, but will be increased in rats given quinpirole, a D 2-receptor agonist. Methods d-Amphetamine (5.0 mg/kg i.p.), quinpirole (1.0 mg/kg i.v.), or saline was administered to unanesthetized rats having a chronic unilateral lesion of the substantia nigra. AA incorporation coefficients, k* (radioactivity/integrated plasma radioactivity), markers of AA signaling, were measured using quantitative autoradiography in 62 bilateral brain regions following intravenous [1- 14C]AA. Results In rats given saline (baseline), k* was elevated in 13 regions in the lesioned compared with intact hemisphere. Quinpirole increased k* in frontal cortical and basal ganglia regions bilaterally, more so in the lesioned than intact hemisphere. d-Amphetamine increased k* bilaterally but less so in the lesioned hemisphere. Conclusions Increased baseline elevations of k* and increased responsiveness to quinpirole in the lesioned hemisphere are consistent with their higher D 2-receptor and cPLA 2 activity levels, whereas reduced responsiveness to D-amphetamine is consistent with dropout of pre-synaptic elements containing the DAT. In vivo imaging of AA signaling using dopaminergic drugs can identify pre- and post-synaptic DA changes in animal models of Parkinson's disease.

Occludin is overexpressed in Alzheimer's disease and vascular dementia

The tight junctions (TJs) are key players in the control of blood-brain barrier (BBB) properties, the most complex TJs in the vascular system being found in the endothelial cells of brain capillaries. One of the main TJs proteins is occludin, which anchors plasma membranes of neighbour cells and is present in large amounts in the brain endothelia. Previous studies demonstrated that disruption of BBB in various pathological situations associates with changes in occludin expression, and this change could be responsible for malfunction of BBB. Therefore in this study, applying an immunohistochemical approach, we decided to explore the occludin expression in frontal cortex (FC) and basal ganglia in ageing control, Alzheimer's disease (AD), and vascular dementia (VD) brains, as far as all these pathologies associate microangiopathy and disruption of BBB. Strikingly, we found selected neurons, astrocytes and oligodendrocytes expressing occludin, in all cases studied. To estimate the number of occludin-expressing neurons, we applied a stereological approach with random systematic sampling and the unbiased optical fractionator method. We report here a significant increase in ratio of occludin-expressing neurons in FC and basal ganglia regions in both AD and VD as compared to ageing controls. Within the cerebral cortex, occludin was selectively expressed by pyramidal neurons, which are the ones responsible for cognitive processes and affected by AD pathology. Our findings could be important in unravelling new pathogenic pathways in dementia disorders and new functions of occludin and TJs.

Ischaemic stroke, factor V Leiden heterozygosity and left atrial thrombosis in sinus rhythm: a case report

We describe a 63-year-old man in sinus rhythm (SR) with an ischaemic stroke involving basal ganglia region on the right side. The patient was known to be heterozygous for factor V Leiden (FVL) mutation. On diagnostic work-up, no arterial sources of embolism were found. Transoesophageal echocardiography evidenced a left atrial (LA) thrombosis without relevant cardiopathies. LA thrombosis is generally associated to atrial fibrillation, atrial enlargement, mitral valve stenosis and left ventricular dysfunction, whereas mitral regurgitation is considered protective. To our knowledge, this is the first report of cardioembolic stroke related to a LA thrombosis in a patient in SR without risk factors for thrombus formation except for FVL heterozygosity.

Functional connectivity in the pharmacologically activated brain: Resolving networks of correlated responses to d‐amphetamine

We investigated the functional connectivity structure underlying the widespread relative cerebral blood volume (rCBV) response to d-amphetamine in the rat brain by systematically analyzing the intersubject correlations between the response amplitudes in 48 atlas-defined brain structures. A cluster analysis resolved three distinct networks of brain regions that exhibited closely coupled responses: one corresponding to primary dopamine projections from the midbrain to the striatum, a second consisting predominantly of forebrain cortical and basal ganglia regions that share a widespread correlation pattern resembling the univariate group response, and a third including structures in the periventricular dopamine system. These results suggest that different functional networks underlie the brain's response to d-amphetamine. This approach may provide important new insights regarding the central systems that underlie pharmacological action.

Apathy and the basal ganglia

We should like to emphasize the following points: 1. Apathy is defined here as a quantified and observable behavioral syndrome consisting in a quantitative reduction of voluntary (or goal-directed) behaviors; 2. Therefore, apathy occurs when the systems that generate and control voluntary actions are altered; 3. These systems are mostly represented by the different subregions embedded in the Prefrontal cortex (PFC) and in the basal ganglia regions that are closely connected with the PFC; 4. In consequence, clinically, apathy is a prefrontal syndrome either due to direct lesions of the PFC or to lesions of basal ganglia areas that are closely related to the PFC; 5. Apathy is not a single entity but rather heterogeneous. Several different mechanisms may lead to apathy; Because there are several anatomical-functional prefrontal-basal ganglia circuits, the underlying mechanisms responsible for apathy may differ according to which prefrontal-basal ganglia circuit is affected; 6. In this context, apathy is the macroscopic results of the disruption of one or several elementary steps necessary for goal-directed behavior that are subserved by different prefrontal-basal ganglia circuits; 7. Intense apathy is related to caudate nucleus and GPi, disrupting associative and limbic pathways from/to the PFC; 8. in progressive supranuclear palsy (PSP) and focal lesions (caudate nuclei, GPi), apathy may be due to a loss of PFC activation; 9. In Parkinson's disease (PD), apathy may be due to a loss of signal focalization; 10. More globally, we propose that apathy may be explained by the impact of lesions or dysfunctions of the BG, because these lesions or dysfunctions lead to a loss of amplification of the relevant signal and/or to a loss of temporal and spatial focalization, both of which result in a diminished extraction of the relevant signal within the frontal cortex, thereby inhibiting the capacity of the frontal cortex to select, initiate, maintain and shift programs of action.

Hemichorea associated with polycythaemia vera

Chorea is a rare complication of polycythaemia vera. Polycythaemic chorea occurs predominantly in females and usually in generalised form. We present a 66-year-old woman with acute onset hemichorea-ballism with no vascular pathology in the basal ganglia region. A clear relationship was observed between the onset of chorea and worsening of haematological parameters in the patient. After repeated phlebotomies the patient's clinical status was improved. Polycythaemic chorea must be considered, especially in the elderly, as early diagnosis leads to effective treatment and prevention of complications.