Real time and delayed effects of subcortical low intensity focused ultrasound.

Deep brain nuclei are integral components of large-scale circuits mediating important cognitive and sensorimotor functions. However, because they fall outside the domain of conventional non-invasive neuromodulatory techniques, their study has been primarily based on neuropsychological models, limiting the ability to fully characterize their role and to develop interventions in cases where they are damaged. To address this gap, we used the emerging technology of non-invasive low-intensity focused ultrasound (LIFU) to directly modulate left lateralized basal ganglia structures in healthy volunteers. During sonication, we observed local and distal decreases in blood oxygenation level dependent (BOLD) signal in the targeted left globus pallidus (GP) and in large-scale cortical networks. We also observed a generalized decrease in relative perfusion throughout the cerebrum following sonication. These results show, for the first time using functional MRI data, the ability to modulate deep-brain nuclei using LIFU while measuring its local and global consequences, opening the door for future applications of subcortical LIFU.

Abnormal Vasculature Development in Zebrafish Embryos with Reduced Expression of Pantothenate Kinase 2 Gene.

Mutations in pank2 gene encoding pantothenate kinase 2 determine a pantothenate kinase-associated neurodegeneration, a rare disorder characterized by iron deposition in the globus pallidus. To extend our previous work, we performed microinjections of a new pank2-specific morpholino to zebrafish embryos and thoroughly analyzed vasculature development. Vessels development was severely perturbed in the head, trunk, and tail, where blood accumulation was remarkable and associated with dilation of the posterior cardinal vein. This phenotype was specific as confirmed by p53 expression analysis and injection of the same morpholino in pank2-mutant embryos. We can conclude that pank2 gene is involved in vasculature development in zebrafish embryos. The comprehension of the underlining mechanisms could be of relevance for understanding of pantothenate kinase-associated neurodegeneration.

Hemiplegia and bilateral globus pallidus infarcts after carbon monoxide poisoning: case report.

The vast clinical manifestations of carbon monoxide (CO) poisoning can involve the neurological, neuropsychological and cardiac systems as well as others. In this case report, we describe our management of a 64-year-old woman exposed to CO in her apartment. Her presentation was unusual in that she had symmetric globus pallidus lesions, no evidence of thrombosis, but the lateralizing neurologic manifestation of severe hemiplegia.

Clinical significance of blood supply to the internal capsule and basal ganglia.

Although the general vascular supply of the basal ganglia and internal capsule is well known, precise data are lacking regarding the variations of the vascular territories in the two regions. Twelve hemispheres were studied following an injection of coloured ink into the main cerebral arteries, namely the anterior cerebral (ACA), middle cerebral (MCA), anterior choroidal (AChA) and posterior cerebral artery (PCA). Serial sections of the injected hemispheres were taken in the axial or coronal plane. In 75% of the hemispheres, ACA perforators were seen to supply the inferomedial part of the head of the caudate nucleus and the anterior limb of the internal capsule, as well as the anterior and inferior portions of the putamen and globus pallidus. The MCA vessels perfused the superolateral part of the head and body of the caudate nucleus, the superior part of the entire internal capsule, most of the putamen and part of the globus pallidus. The AChA perforators perfused the medial segment of the globus pallidus, the inferior part of the posterior limb, the retrolenticular and sublenticular portions of the internal capsule, and occasionally its genu. The same segment of the globus pallidus and the inferior part of the genu of the internal capsule were most likely supplied by the perforators of the internal carotid artery. A predominance of ACA territory was noticed in one specimen (8.33%) and a predominance of MCA territory in two specimens (16.67%). The obtained anatomical data may help radiologic determination of perforators involved in ischemic events, as well as a better understanding of the neurological deficits in the same events.

Striatal and Pallidal Activation during Reward Modulated Movement Using a Translational Paradigm.

Human neuroimaging studies of reward processing typically involve tasks that engage decision-making processes in the dorsal striatum or focus upon the ventral striatum's response to feedback expectancy. These studies are often compared to the animal literature; however, some animal studies include both feedback and nonfeedback events that activate the dorsal striatum during feedback expectancy. Differences in task parameters, movement complexity, and motoric effort to attain rewards may partly explain ventral and dorsal striatal response differences across species. We, therefore, used a target capture task during functional neuroimaging that was inspired by a study of single cell modulation in the internal globus pallidus during reward-cued, rotational arm movements in nonhuman primates. In this functional magnetic resonance imaging study, participants used a fiberoptic joystick to make a rotational response to an instruction stimulus that indicated both a target location for a capture movement and whether or not the trial would end with feedback indicating either a small financial gain or a neutral outcome. Portions of the dorsal striatum and pallidum demonstrated greater neural activation to visual cues predicting potential gains relative to cues with no associated outcome. Furthermore, both striatal and pallidal regions displayed a greater response to financial gains relative to neutral outcomes. This reward-dependent modulation of dorsal striatal and pallidal activation in a target-capture task is consistent with findings from reward studies in animals, supporting the use of motorically complex tasks as translational paradigms to investigate the neural substrates of reward expectancy and outcome in humans.

Altered striatal and pallidal connectivity in cervical dystonia.

Cervical dystonia is a neurological movement disorder characterized by involuntary, abnormal movements of the head and neck. Injecting the overactive muscles with botulinum toxin is the gold standard treatment, supported by good evidence (Delnooz and van de Warrenburg in Ther Adv Neurol Disord 5:221-240, 2012). Current views on its pathophysiology support a role for the basal ganglia, although there are probably more widespread abnormalities in brain networks in which the basal ganglia are important nodes. Their precise role in cervical dystonia is unknown. We sought to address this issue by examining alterations in the functional connectivity of the basal ganglia. Using resting-state functional MRI and functional parcellations, we investigated functional connectivity in cervical dystonia patients and age- and gender-matched healthy controls. We mapped connectivity voxel-wise across the striatum and the globus pallidus for a set of brain masks, defined from well-known resting-state networks. Scans were repeated before and after botulinum toxin injections to see whether connectivity abnormalities were perhaps restored. We found that in cervical dystonia (1) the right mid-dorsal putamen and right external globus pallidus have reduced connectivity with a network comprising left fronto-parietal regions; and (2) the bilateral anterior putamen shows a trend towards enhanced connectivity with a network comprising sensorimotor areas. We observed that botulinum toxin treatment induces reorganization between a network comprising mainly (pre)frontal areas and (1) the right mid-ventral striatum and (2) the right external globus pallidus. Cervical dystonia patients have altered functional connectivity between the basal ganglia and some cortical regions that are part of specific brain networks that in part are influenced by botulinum toxin treatment. These connectivity abnormalities may be primary as well as secondary, perhaps compensatory, phenomena.

The ventral pallidum and orbitofrontal cortex support food pleasantness inferences.

Food advertisements often promote choices that are driven by inferences about the hedonic pleasures of eating a particular food. Given the individual and public health consequences of obesity, it is critical to address unanswered questions about the specific neural systems underlying these hedonic inferences. For example, although regions such as the orbitofrontal cortex (OFC) are frequently observed to respond more to pleasant food images than less hedonically pleasing stimuli, one important hedonic brain region in particular has largely remained conspicuously absent among human studies of hedonic response to food images. Based on rodent research demonstrating that activity in the ventral pallidum underlies the hedonic pleasures experienced upon eating food rewards, one might expect that activity in this important 'hedonic hotspot' might also track inferred food pleasantness. To date, however, no human studies have assessed this question. We thus asked human subjects to undergo fMRI and make item-by-item ratings of how pleasant it would be to eat particular visually perceived foods. Activity in the ventral pallidum was strongly modulated with pleasantness inferences. Additionally, activity within a region of the orbitofrontal cortex that tracks the pleasantness of tastes was also modulated with inferred pleasantness. Importantly, the reliability of these findings is demonstrated by their replication when we repeated the experiment at a new site with new subjects. These two experiments demonstrate that the ventral pallidum, in addition to the OFC, plays a central role in the moment-to-moment hedonic inferences that influence food-related decision-making.

[Hemiparkinsonism due to a solitary infarction of the right external segment of the globus pallidus: a case report].

Three months prior to presentation, a 76-year-old woman suffered from insomnia and was prescribed some antidepressants and hypnotics. At that time, brain MRI showed no cerebral infarcts. Having developed an action tremor of the left hand, bradykinesia, and unstable gait, she visited our hospital. Neurological examination revealed rigidity of the neck and left limbs, clumsiness of the left hand, action tremor, and decreasing swing of the left arm while walking. 123I-metaiodobenzylguanidine scintigraphy showed no decrease of the heart/mediastinum ratio. The second MRI showed an old cerebral infarct located just in the right external segment of the globus pallidus. Since drug-induced parkinsonism was suspected, paroxetine and trazodone were discontinued, but her symptoms did not improve. We concluded that her hemiparkinsonism was due to the cerebral infarct in the right external segment of the globus pallidus, because her symptoms did not respond to dopamine agonist and L-dopa therapy, and the onset of symptoms corresponded with the time of appearance of the cerebral infarct. This is a rare case that is important for understanding the mechanism of parkinsonism.

Whole-brain susceptibility mapping at high field: a comparison of multiple- and single-orientation methods.

Optimisation and comparison of the performance of three different methods for calculating three-dimensional susceptibility maps of the whole brain from gradient-echo (phase and modulus) image data acquired at 7 T is described. The methods studied are a multiple-orientation method in which image data acquired with the head at several different angles to the main field are combined and two methods which use data acquired at a single orientation: the first of these is based on exclusion of some k-space data from the calculation (through thresholding of the dipolar field kernel), while the second incorporates a regularisation method that is based on using information from the modulus images. The methods were initially optimised via analysis of data from a phantom containing different compartments of known susceptibility. As part of this work, a novel high-pass filtering methodology was introduced to remove background fields from field maps based on phase data. The optimised methods were successfully applied to high-resolution (0.7 mm isotropic) whole-brain modulus and phase data acquired in vivo from five healthy male subjects, 25-30 years of age. The multiple-orientation method yielded high quality susceptibility maps, out-performing the single-orientation methods. Venous blood vessels as well as the substantia nigra and globus pallidus brain regions showed particularly high positive susceptibility offsets relative to surrounding tissue, consistent with high deoxyhemoglobin and non-heme iron content, respectively. To compare the performance of the different methods, regions of interest were drawn in deep grey matter structures and in cortical grey and white matter. The threshold-based approach was fast and simple to use, but underestimated susceptibility differences and showed significant artefacts due to noise amplification in difficult regions of k-space. The regularised single-orientation method yielded contrast dependent on the choice of spatial priors, but demonstrated the potential to yield susceptibility maps of a similar quality to those calculated using data acquired at multiple orientations to the field.

Anomalous medial origin of the anterior choroidal artery with associated aneurysm.

Injury to the anterior choroidal artery (AchA) can be devastating owing to the importance of the territory it supplies. The AchA is a known site of aneurysm formation, and is often exposed during various surgical and endovascular procedures. We report a patient with an aneurysm at the origin of the AchA, and an anomalous medial take off of the artery from the internal carotid artery, then a sharp lateral turn followed by a normal course toward the choroidal fissure, unreported to date to our knowledge. The aneurysm was treated successfully by endovascular therapy. The typical anatomy of the AchA, and reported variations in its origin are discussed. Thorough knowledge of the normal cerebrovascular anatomy and attention to variations play an important role in the successful management of patients with neurological vascular conditions.

Contrasting changes in cortical activation induced by acute high-frequency stimulation within the globus pallidus in Parkinson's disease.

Continuous stimulation of the globus pallidus (GP) has been shown to be an effective treatment for Parkinson's disease (PD). We used the fact that the implanted quadripolar leads contain electrodes within the GPi and GPe to investigate the clinical effects of acute high-frequency stimulation applied in these nuclei and changes in regional cerebral blood flow (rCBF) as an index of synaptic activity. In five patients treated by chronic GP stimulation, we compared the effects on PD symptoms and the changes in rCBF at rest and during paced right-hand movements, with and without left GPe or GPi stimulation. Although improving contralateral rigidity and akinesia, left GPe stimulation decreased rCBF in the left cerebellum and lateral premotor cortex at rest and significantly increased it in the left primary sensorimotor cortex (SM1) during movement. In contrast, left ventral GPi stimulation, which improved rigidity and worsened akinesia, decreased rCBF in the left SM1, premotor area, anterior cingulum, and supplementary motor area but did not modify the movement-related activation. GPe stimulation seems to result in a reduced activity of motor-related areas and the facilitation of motor cortex activation during movement, the latter component being absent during GPi stimulation, and this may explain the observed worsening of akinesia.

Abnormal regional cerebral blood flow in cognitively normal elderly subjects with hypertension.

BACKGROUND AND PURPOSE: The purpose of this study was to examine regional cerebral blood flow (rCBF) in normal cognitive-performing subjects with hypertension (HTN) using continuous arterial spin-labeled MRI. The most common explanation for the effect of blood pressure on cognition is that HTN increases the risk of cerebrovascular disease, and it may increase the risk for Alzheimer disease possibly through small vessel disease, ischemia, oxidative stress, and inflammation. However, few studies to date have examined the rCBF of cognitively normal subjects with HTN in population-based cohorts, and none have used continuous arterial spin-labeled MRI. This is a noninvasive technique that does not require either injections or ionizing radiation and can measure absolute rCBF rates over the entire brain. METHODS: rCBF was measured at 1.5 T using continuous arterial spin-labeled MRI in 41 cognitively normal subjects who were participating in the Cardiovascular Health Study Cognition Study. A deformable atrophy-corrected registration method was used to warp the rCBF maps to the standard colin27 brain space. Image and cluster-based statistical analyses were performed between subject groups. RESULTS: Cognitively normal subjects with HTN (n=19) had decreased rCBF in the putamen, globus pallidus, bilaterally, and in the left hippocampus compared with normotensives (n=22). In addition, decreased rCBF was observed in the right and left anterior cingulate gyrus with extension to the subcallosal region, left posterior cingulate gyrus and medial precuneus, left lateral inferior and superior frontal, and inferior parietal, left orbitofrontal, and left superior temporal cortices. CONCLUSIONS: rCBF is affected in normal subjects with HTN, not only in the subcortical regions, but also in limbic and paralimbic structures. We hypothesize that the HTN creates a vulnerability state for the development of neurodegenerative disorders, especially Alzheimer disease.

High frequency deep brain stimulation: what are the therapeutic mechanisms?

High frequency deep brain stimulation (HFS) used to treat the symptoms of Parkinson's disease (PD) was first assumed to act by reducing an excessive tonic GABAergic inhibitory output from the internal globus pallidus (GPi). Stimulation in GPi might produce this directly by mechanisms such as depolarization block or activation of presynaptic inhibitory fibers, and the same mechanisms evoked by HFS in the subthalamic nucleus (STN) could reduce the excitatory action of STN on GPi neurons. Although somatic recordings from neurons near the stimulation site may appear to support this potential mechanism, the action downstream from the site of stimulation often is not consistent with this interpretation. A more parsimonious explanation for the similar effects of HFS in STN or GPi and a lesion of either of these structures is that both HFS and pallidotomy interrupt an abnormal pattern of firing in cortico-basal ganglia-thalamocortical loops that is responsible for the symptoms of PD.

Role of individual basal ganglia nuclei in force amplitude generation.

The basal ganglia-thalamo-cortical loop is an important neural circuit that regulates motor control. A key parameter that the nervous system regulates is the level of force to exert against an object during tasks such as grasping. Previous studies indicate that the basal ganglia do not exhibit increased activity with increasing amplitude of force, although these conclusions are based mainly on the putamen. The present study used functional magnetic resonance imaging to investigate which regions in the basal ganglia, thalamus, and motor cortex display increased activity when producing pinch-grip contractions of increasing force amplitude. We found that the internal portion of the globus pallidus (GPi) and subthalamic nucleus (STN) had a positive increase in percent signal change with increasing force, whereas the external portion of the globus pallidus, anterior putamen, posterior putamen, and caudate did not. In the thalamus we found that the ventral thalamic regions increase in percent signal change and activation volume with increasing force amplitude. The contralateral and ipsilateral primary motor/somatosensory (M1/S1) cortices had a positive increase in percent signal change and activation volume with increasing force amplitude, and the contralateral M1/S1 had a greater increase in percent signal change and activation volume than the ipsilateral side. We also found that deactivation did not change across force in the motor cortex and basal ganglia, but that the ipsilateral M1/S1 had greater deactivation than the contralateral M1/S1. Our findings provide direct evidence that GPi and STN regulate the amplitude of force output. These findings emphasize the heterogeneous role of individual nuclei of the basal ganglia in regulating specific parameters of motor output.

Disgust sensitivity predicts the insula and pallidal response to pictures of disgusting foods.

The anterior insula has been implicated in coding disgust from facial, pictorial and olfactory cues, and in the experience of this emotion. Personality research has shown considerable variation in individuals' trait propensity to experience disgust ('disgust sensitivity'). Our study explored the neural expression of this trait, and demonstrates that individual variation in disgust sensitivity is significantly correlated with participants' ventroanterior insular response to viewing pictures of disgusting, but not appetizing or bland, foods. Similar correlations were also seen in the pallidum and orofacial regions of motor and somatosensory cortices. Our results also accord with comparative research showing an anterior to posterior gradient in the rat pallidum reflecting increased 'liking' of foods [Smith, K. S. and Berridge, K. C. (2005) J. Neurosci., 25, 849-8637].

[Validity of vascular depression as a specific diagnostic: a review]. / Validité du concept de dépression vasculaire: une revue de la littérature.

INTRODUCTION: A number of authors have suggested that cerebrovascular disease may predispose, precipitate, or perpetuate some geriatric depressive syndromes. These "vascular depressions" may result from damage of striato-pallido-thalamo-cortical pathways which frequently occurs in cerebrovascular disease. METHOD: We have searched the English and French literature published between 1996 (when the "vascular depression" hypothesis was first stated) and December 2004 through the Medline computer database and examined the validity of the concept of "vascular depression" thanks to four levels of validity: face validity, descriptive validity, construct validity and predictive validity. The face validity is the extent to which experts agree about the existence of a nosological entity. RESULTS: The reviews published in this field broadly support the concept of "vascular depression" as a specific disorder. However many authors highlighted the fact that depression has been shown to precede vascular diseases and that depression and vascular diseases may both share some pathogenic or genetic determinants. These interactive and co-morbid relationships between depression and cerebrovascular diseases are difficult to disentangle. The descriptive validity refers to the degree of the clinical specificity of a disorder. It appears only moderate regarding the clinical studies carried out on this issue. However, a late-onset, the absence of a family history of mental illness, the lack of insight, lassitude, psychomotor retardation, a greater disability and particular neuropsychological dysfunctions may be associated with vascular depression. The construct validity, which refers to the degree to which the physiopathological processes involved in an illness are understood, appears difficult to establish because of the complex interactive relationships between cerebrovascular disease and depression. However, cerebrovascular diseases may contribute to the occurrence of depressive symptoms independently of its psychosocial burden. The predictive validity refers to the degree to which a syndrome is characterized by a specific response to treatment or a specific natural history. As regards response to treatment, vascular depression appears rather specific in the sense of a worse response to antidepressants and electroconvulsive therapy. The studies on the natural history of vascular depression lead to inconsistent results. According to some authors, this relative resistance to treatment may be explained by structural rather than functional, and thus potentially irreversible disruption in neural networks. CONCLUSION: In conclusion, the systematic review of the validity of vascular depression broadly supports this concept. However, further studies are needed to decipher the relationships between depression and cerebrovascular disease. Finally, we suggest that it could be more relevant for future researches in this field if the diagnostic criteria for vascular depression were narrowed and required the presence of both neuro-imaging changes and cerebrovascular disease.

Is it possible to predict the long-term response to venlafaxine with the use of biological markers and psychophysiological methods?

INTRODUCTION: The present study investigated whether it is possible to predict the medium term response to venlafaxine using biological markers and psychophysiological methods. MATERIAL: Fourteen (14) patients aged 21-60 years suffering from Major Depression according to DSM-IV were included in the study. METHODS: The SCAN v 2.0 and the IPDE were used to assist clinical diagnosis. Patients were investigated with electrooculogram (EOG), Pattern-Reversal Visual Evoked Potentials (PR-VEPs), Dexamethasone Suppression Test (DST), D-fenfluramine Challenge Test, and brain Single Photon Emission Tomography (SPECT). Venlafaxine 150-225 mg per os daily was administered. The follow-up period was 2 years. STATISTICAL ANALYSIS: Chi-square test and ANOVA were used for the analysis of data. RESULTS: There was a lower left globus pallidus regional cerebral blood flow in patients with better response. On the contrary, chronic patients were closer to normality. DISCUSSION: The results of the current study provide preliminary evidence concerning our ability to predict response to venlafaxine and to understand its way of action.

Evaluation of basal ganglia haemodynamic changes with perfusion-weighted magnetic resonance imaging in patients with Parkinson's disease.

PURPOSE: The aim of our study was to assess the regional cerebral blood flow (rCBF) of basal ganglia and thalami in patients with Parkinson's disease (PD) using perfusion-weighted magnetic resonance imaging (PW-MRI). MATERIAL AND METHODS: Twenty subjects affected by idiopathic PD according to the United Kingdom Brain Bank criteria were enrolled in the study. Twenty normal subjects matched for age and gender were included as controls. After 20-day therapy withdrawal, the PD patients underwent PW-MRI. The rCBF was calculated both in patients and in controls. The regions of interest were manually positioned on rCBF maps over the caudate nucleus, the putamen, the external and internal globus pallidus, and over the ventrolateral nucleus of the thalamus. Data were normalised with those obtained from parieto-occipital white matter (POWM). Statistical analysis was performed using a parametric ANOVA test. RESULTS: Patients showed a significant (p<0.01) interhemispheric asymmetry; rCBF values were higher on the more severely affected side. Controls showed no interhemispheric asymmetry. CONCLUSION: Our study suggests that PW-MRI is a valuable tool for assessing haemodynamic changes in PD patients. Haemodynamic change pattern may be useful in the early diagnosis of PD.

Normalizing motor-related brain activity: subthalamic nucleus stimulation in Parkinson disease.

OBJECTIVE: To test whether therapeutic unilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) in patients with Parkinson disease (PD) leads to normalization in the pattern of brain activation during movement execution and control of movement extent. METHODS: Six patients with PD were imaged off medication by PET during performance of a visually guided tracking task with the DBS voltage programmed for therapeutic (effective) or subtherapeutic (ineffective) stimulation. Data from patients with PD during ineffective stimulation were compared with a group of 13 age-matched control subjects to identify sites with abnormal patterns of activation. Conjunction analysis was used to identify those areas in patients with PD where activity normalized when they were treated with effective stimulation. RESULTS: For movement execution, effective DBS caused an increase of activation in the supplementary motor area (SMA), superior parietal cortex, and cerebellum toward a more normal pattern. At rest, effective stimulation reduced overactivity of SMA. Therapeutic stimulation also induced reductions of movement related "overactivity" compared with healthy subjects in prefrontal, temporal lobe, and basal ganglia circuits, consistent with the notion that many areas are recruited to compensate for ineffective motor initiation. Normalization of activity related to the control of movement extent was associated with reductions of activity in primary motor cortex, SMA, and basal ganglia. CONCLUSIONS: Effective subthalamic nucleus stimulation leads to task-specific modifications with appropriate recruitment of motor areas as well as widespread, nonspecific reductions of compensatory or competing cortical activity.