Automatic Quantitative MRI Texture Analysis in Small-for-Gestational-Age Fetuses Discriminates Abnormal Neonatal Neurobehavior

Background

We tested the hypothesis whether texture analysis (TA) from MR images could identify patterns associated with an abnormal neurobehavior in small for gestational age (SGA) neonates.

Methods

Ultrasound and MRI were performed on 91 SGA fetuses at 37 weeks of GA. Frontal lobe, basal ganglia, mesencephalon and cerebellum were delineated from fetal MRIs. SGA neonates underwent NBAS test and were classified as abnormal if ≥1 area was <5^th centile and as normal if all areas were >5^th centile. Textural features associated with neurodevelopment were selected and machine learning was used to model a predictive algorithm.

Results

Of the 91 SGA neonates, 49 were classified as normal and 42 as abnormal. The accuracies to predict an abnormal neurobehavior based on TA were 95.12% for frontal lobe, 95.56% for basal ganglia, 93.18% for mesencephalon and 83.33% for cerebellum.

Conclusions

Fetal brain MRI textural patterns were associated with neonatal neurodevelopment. Brain MRI TA could be a useful tool to predict abnormal neurodevelopment in SGA.     

Estimating the Confidence Level of White Matter Connections Obtained with MRI Tractography

Background

Since the emergence of diffusion tensor imaging, a lot of work has been done to better understand the properties of diffusion MRI tractography. However, the validation of the reconstructed fiber connections remains problematic in many respects. For example, it is difficult to assess whether a connection is the result of the diffusion coherence contrast itself or the simple result of other uncontrolled parameters like for example: noise, brain geometry and algorithmic characteristics.

Methodology/Principal Findings

In this work, we propose a method to estimate the respective contributions of diffusion coherence versus other effects to a tractography result by comparing data sets with and without diffusion coherence contrast. We use this methodology to assign a confidence level to every gray matter to gray matter connection and add this new information directly in the connectivity matrix.

Conclusions/Significance

Our results demonstrate that whereas we can have a strong confidence in mid- and long-range connections obtained by a tractography experiment, it is difficult to distinguish between short connections traced due to diffusion coherence contrast from those produced by chance due to the other uncontrolled factors of the tractography methodology.     

A Rat Model of Hemidystonia Induced by 3-Nitropropionic Acid

Objective

Secondary dystonia commonly presents as hemidystonia and is often refractory to current treatments. We aimed to establish an inducible rat model of hemidystonia utilizing 3-nitropropionic acid (3-NP) and to determine the pathophysiology of this model.

Methods

Two different doses of 3-NP were stereotactically administered into the ipsilateral caudate putamen (CPu) of Wistar rats. Behavioral changes and alterations in the neurotransmitter levels in the basal ganglia were analyzed. We also performed an electromyogram, 7.0-T magnetic resonance imaging and transmission electron microscopy examination to determine the pathophysiology of the model.

Results

In the CPu region, 3-NP produced mitochondrial cristae rupture, axonal degeneration, increased excitatory synaptic vesicles and necrosis. The extracellular concentrations of excitatory amino acids increased, whereas the inhibitory amino acids decreased in the CPu. Furthermore, an imbalance of neurotransmitters was found in other regions of the basal ganglia with the exception of the external globus pallidus. This study demonstrated that 3-NP administration results in CPu damage, and combined with a neurotransmitter imbalance in the basal ganglia, it produces specific neurobehavioral changes in rats. Right limb (contralateral side of CPu lesion) and trunk dystonic postures, shortened step length and ipsiversive dystonic posturing were observed in these rats. Furthermore, EMG recordings confirmed that co-contraction of the agonist and antagonist muscles could be seen for several seconds in right limbs.

Conclusions

Stereotactic injection of 3-NP into the ipsilateral CPu of rats established an inducible model for hemidystonia. This effect might result from an imbalance of neurotransmitter levels, which induce dysfunctional activity of the basal ganglia mainly via the cortico-striato-GPi direct pathway. Symptoms in this model were present for 1 week. Activation of the cortico-striato-GPe indirect pathway and rebalance of neurotransmitters may lead to recovery. This rat model may be a suitable tool used to understand and further investigate the pathophysiology of dystonia.     

Optic Radiation Fiber Tractography in Glioma Patients Based on High Angular Resolution Diffusion Imaging with Compressed Sensing Compared with Diffusion Tensor Imaging - Initial Experience

Objective

Up to now, fiber tractography in the clinical routine is mostly based on diffusion tensor imaging (DTI). However, there are known drawbacks in the resolution of crossing or kissing fibers and in the vicinity of a tumor or edema. These restrictions can be overcome by tractography based on High Angular Resolution Diffusion Imaging (HARDI) which in turn requires larger numbers of gradients resulting in longer acquisition times. Using compressed sensing (CS) techniques, HARDI signals can be obtained by using less non-collinear diffusion gradients, thus enabling the use of HARDI-based fiber tractography in the clinical routine.

Methods

Eight patients with gliomas in the temporal lobe, in proximity to the optic radiation (OR), underwent 3T MRI including a diffusion-weighted dataset with 30 gradient directions. Fiber tractography of the OR using a deterministic streamline algorithm based on DTI was compared to tractography based on reconstructed diffusion signals using HARDI+CS.

Results

HARDI+CS based tractography displayed the OR more conclusively compared to the DTI-based results in all eight cases. In particular, the potential of HARDI+CS-based tractography was observed for cases of high grade gliomas with significant peritumoral edema, larger tumor size or closer proximity of tumor and reconstructed fiber tract.

Conclusions

Overcoming the problem of long acquisition times, HARDI+CS seems to be a promising basis for fiber tractography of the OR in regions of disturbed diffusion, areas of high interest in glioma surgery.     

Neuroanatomical Correlates of Intelligence in Healthy Young Adults: The Role of Basal Ganglia Volume

Background

In neuropsychiatric diseases with basal ganglia involvement, higher cognitive functions are often impaired. In this exploratory study, we examined healthy young adults to gain detailed insight into the relationship between basal ganglia volume and cognitive abilities under non-pathological conditions.

Methodology/Principal Findings

We investigated 137 healthy adults that were between the ages of 21 and 35 years with similar educational backgrounds. Magnetic resonance imaging (MRI) was performed, and volumes of basal ganglia nuclei in both hemispheres were calculated using FreeSurfer software. The cognitive assessment consisted of verbal, numeric and figural aspects of intelligence for either the fluid or the crystallised intelligence factor using the intelligence test Intelligenz-Struktur-Test (I-S-T 2000 R). Our data revealed significant correlations of the caudate nucleus and pallidum volumes with figural and numeric aspects of intelligence, but not with verbal intelligence. Interestingly, figural intelligence associations were dependent on sex and intelligence factor; in females, the pallidum volumes were correlated with crystallised figural intelligence (r = 0.372, p = 0.01), whereas in males, the caudate volumes were correlated with fluid figural intelligence (r = 0.507, p = 0.01). Numeric intelligence was correlated with right-lateralised caudate nucleus volumes for both females and males, but only for crystallised intelligence (r = 0.306, p = 0.04 and r = 0.459, p = 0.04, respectively). The associations were not mediated by prefrontal cortical subfield volumes when controlling with partial correlation analyses.

Conclusions/Significance

The findings of our exploratory analysis indicate that figural and numeric intelligence aspects, but not verbal aspects, are strongly associated with basal ganglia volumes. Unlike numeric intelligence, the type of figural intelligence appears to be related to distinct basal ganglia nuclei in a sex-specific manner. Subcortical brain structures thus may contribute substantially to cognitive performance.     

Tractography of the Brainstem in Major Depressive Disorder Using Diffusion Tensor Imaging

Background

The brainstem is the main region that innervates neurotransmitter release to the Hypothalamic-Pituitary Adrenal (HPA) axis and fronto-limbic circuits, two key brain circuits found to be dysfunctional in Major Depressive Disorder (MDD). However, the brainstem’s role in MDD has only been evaluated in limited reports. Using Diffusion Tensor Imaging (DTI), we investigated whether major brainstem white matter tracts that relate to these two circuits differ in MDD patients compared to healthy controls.

Methods

MDD patients (n = 95) and age- and gender-matched controls (n = 34) were assessed using probabilistic tractography of DTI to delineate three distinct brainstem tracts: the nigrostriatal tract (connecting brainstem to striatum), solitary tract (connecting brainstem to amygdala) and corticospinal tract (connecting brainstem to precentral cortex). Fractional anisotropy (FA) was used to measure the white matter integrity of these tracts, and measures were compared between MDD and control participants.

Results

MDD participants were characterized by a significant and specific decrease in white matter integrity of the right solitary tract (p<0.009 using independent t-test), which is a “bottom up” afferent pathway that connects the brainstem to the amygdala. This decrease was not related to symptom severity.

Conclusions

The results provide new evidence to suggest that structural connectivity between the brainstem and the amygdala is altered in MDD. These results are interesting in light of predominant theories regarding amygdala-mediated emotional reactivity observed in functional imaging studies of MDD. The characterization of altered white matter integrity in the solitary tract in MDD supports the possibility of dysfunctional brainstem-amygdala connectivity impacting vulnerable circuits in MDD.     

Long-stay psychiatric patients: a prospective study revealing persistent antipsychotic-induced movement disorder

Objective

The purpose of this study was to assess the frequency of persistent drug-induced movement disorders namely, tardive dyskinesia (TD), parkinsonism, akathisia and tardive dystonia in a representative sample of long-stay patients with chronic severe mental illness.

Method

Naturalistic study of 209, mainly white, antipsychotic-treated patients, mostly diagnosed with psychotic disorder. Of this group, the same rater examined 194 patients at least two times over a 4-year period, with a mean follow-up time of 1.1 years, with validated scales for TD, parkinsonism, akathisia, and tardive dystonia.

Results

The frequencies of persistent movement disorders in the sample were 28.4% for TD, 56.2% for parkinsonism, 4.6% for akathisia and 5.7% for tardive dystonia. Two-thirds of the participants displayed at least one type of persistent movement disorder.

Conclusions

Persistent movement disorder continues to be the norm for long-stay patients with chronic mental illness and long-term antipsychotic treatment. Measures are required to remedy this situation.     

Longitudinal deformation-based morphometry reveals spatio-temporal dynamics of brain volume changes in patients with corticobasal syndrome

Background/Objective

Corticobasal syndrome (CBS) is a rare neurodegenerative disorder characterized by a progressive and asymmetric manifestation of cortical and basal-ganglia symptoms of different origin. The spatio-temporal dynamics of cerebral atrophy in CBS is barely known. This study aimed to longitudinally quantify the individual dynamics of brain volume changes in patients with CBS as compared to healthy controls.

Methods

We used deformation-field-based morphometry (DFM) to study volumetric changes of each individual brain in short intervals of a few months. DFM enabled the quantitative analysis of local volume changes without predefining regions of interest in MR images of 6 patients with CBS and 11 matched healthy controls. A total of 64 whole brain 3D-MR-scans were acquired two to eight times over periods of 14 to 26 months. Based on repeated registrations of MR observations to the initial scan, maps of local volume ratio changes were computed.

Results

Compared to controls patients showed significant and increasing volume loss over time in premotor and primary-motor-cortices, somatosensory area 3a, superior parietal areas BA 5/7, and corticospinal tract. Furthermore, significant and asymmetric atrophy was identified in the caudate nucleus head, putamen, pallidum, motor-thalamus and substantia nigra. Temporal lobe was affected in those patients who presented progressive cognitive impairment.

Conclusions

The analysis revealed localized, pathological changes in brains of patients with CBS, which differed significantly from those occurring during aging in healthy controls. As compared to age- and sex-matched controls, brains of CBS patients showed a common degenerating neural network comprising the motor circuit with basal ganglia and motor thalamic nuclei as well as the premotor and primary-motor-cortex.     

Is There a Role for Combined EMG-fMRI in Exploring the Pathophysiology of Essential Tremor and Improving Functional Neurosurgery?

Background

Functional MRI combined with electromyography (EMG-fMRI) is a new technique to investigate the functional association of movement to brain activations. Thalamic stereotactic surgery is effective in reducing tremor. However, while some patients have satisfying benefit, others have only partial or temporary relief. This could be due to suboptimal targeting in some cases. By identifying tremor-related areas, EMG-fMRI could provide more insight into the pathophysiology of tremor and be potentially useful in refining surgical targeting.

Objective

Aim of the study was to evaluate whether EMG-fMRI could detect blood oxygen level dependent brain activations associated with tremor in patients with Essential Tremor. Second, we explored whether EMG-fMRI could improve the delineation of targets for stereotactic surgery.

Methods

Simultaneous EMG-fMRI was performed in six Essential Tremor patients with unilateral thalamotomy. EMG was recorded from the trembling arm (non-operated side) and from the contralateral arm (operated side). Protocols were designed to study brain activations related to voluntary muscle contractions and postural tremor.

Results

Analysis with the EMG regressor was able to show the association of voluntary movements with activity in the contralateral motor cortex and supplementary motor area, and ipsilateral cerebellum. The EMG tremor frequency regressor showed an association between tremor and activity in the ipsilateral cerebellum and contralateral thalamus. The activation spot in the thalamus varied across patients and did not correspond to the thalamic nucleus ventralis intermedius.

Conclusion

EMG-fMRI is potentially useful in detecting brain activations associated with tremor in patients with Essential Tremor. The technique must be further developed before being useful in supporting targeting for stereotactic surgery.     

Factors Related to Executive Dysfunction after Acute Infarct

Aim

The aim of this study was to investigate the association of infarct location with post-stroke executive dysfunction.

Methods

One hundred seventy-seven patients hospitalized with acute infarction were enrolled. General information and NIHSS score at admission were recorded. The infarct site was recorded from magnetic resonance T2-W1 and FLAIR images, and the extent of white matter disease was assessed using the Fazekas score. Seven days after symptoms, executive function was assessed using the validated Chinese version of Mattis Dementia Rating Scale (MDRS) Initiation/Perseveration (I/P) [MDRS I/P].

Results

The average MDRS I/P score of the 177 infarction patients was 24.16±5.21, considerably lower than the average score (32.7±3.1) of a control group of normal individuals. Patients with infarcts in the corona radiata or basal ganglia had significantly lower MDRS I/P scores that those without infarcts at these locations. The number of infarcts in the basal ganglia was also significantly associated with low MDRS I/P scores. Male gender and low NIHSS score were significantly associated with low MDRS I/P score, and high-density lipoprotein cholesterol was significantly associated with high MDRS I/P score. The number of infarcts in areas other than the basal ganglia as well as corona radiata and the extent of white matter disease had no influence on this score.

Conclusions

The number of infarcts in the basal ganglia corona radiata, low NIHSS score, and male gender are significantly and independently related to poor executive function (that is, low MDRS I/P score) after acute infarct.     

Variable Lengths of Stay among Ischemic Stroke Subtypes in Chinese General Teaching Hospitals

Background

Length of stay (LOS) is one of the most important quantitative indexes that measures health service utilization within a hospital. Many studies have examined the association of three major stroke categories with LOS. Our aim is to investigate the differences of LOS among ischemic stroke subtypes, results from which are helpful to healthcare providers and government agencies to improve health care delivery efficiency.

Methodology/Principal Findings

Using the Beijing Municipal Health Bureau’s hospitalization summary reports, we performed a retrospective study among first-ever in-hospital patients with ischemic stroke (ICD-10 I63) in three general teaching hospitals in Beijing, China, from 2006 to 2010 with generalized linear model. In our study, 5,559 patients (female, 36.0%; age, 64.4±12.9 years) were included. The estimated mean LOS of ischemic stroke was 17.4±1.8 days. After adjusting for confounders, LOS of lacunar infarction (14.7 days; p<0.001) and LOS of small cerebral infarction (17.0 days; p = 0.393) were shorter than that of single cerebral infarction (17.9 days, p<0.001). LOS of multi-infarct (19.0 days; p = 0.028), brainstem infarction (19.3 days; p = 0.045), basal ganglia infarction (18.5 days; p = 0.452) and other subtypes of ischemic stroke (18.9 days; p = 0.327) were longer than that of single cerebral infarction.

Conclusions

LOS of ischemic stroke patient differes across single cerebral infarction, lacunar infarction, multi-infarct and brainstem infarction patients. The ascending order of LOS was lacunar infarction, small cerebral infarction, single cerebral infarction, basal ganglia infarction, other subtypes of ischemic stroke, multi-infarct and brainstem infarction.     

Hospital Acquired Pneumonia Is Linked to Right Hemispheric Peri-Insular Stroke

Purpose

Hospital acquired pneumonia (HAP) is a major complication of stroke. We sought to determine associations between infarction of specific brain regions and HAP.

Methods

215 consecutive acute stroke patients with HAP (2003–2009) were carefully matched with 215 non-pneumonia controls by gender, then NIHSS, then age. Admission imaging and binary masks of infarction were registered to MNI-152 space. Regional atlas and voxel-based log-odds were calculated to assess the relationship between infarct location and the likelihood of HAP. An independently validated penalized conditional logistic regression model was used to identify HAP associated imaging regions.

Results

The HAP and control patients were well matched by gender (100%), age (95% within 5-years), NIHSS (98% within 1-point), infarct size, dysphagia, and six other clinical variables. Right hemispheric infarcts were more frequent in patients with HAP versus controls (43.3% vs. 34.0%, p = 0.054), whereas left hemispheric infarcts were more frequent in controls (56.7% vs. 44.7%, p = 0.012); there was no significant difference between groups in the rate of brainstem strokes (p = 1.0). Of the 10 most infarcted regions, only right insular cortex volume was different in HAP versus controls (20 vs. 12 ml, p = 0.02). In univariate analyses, the highest log-odds regions for pneumonia were right hemisphere, cerebellum, and brainstem. The best performing multivariate model selected 7 brain regions of infarction and 2 infarct volume-based variables independently associated with HAP.

Conclusions

HAP is associated with right hemispheric peri-insular stroke. These associations may be related to autonomic modulation of immune mechanisms, supporting recent hypotheses of stroke mediated immune suppression.     

Tractography delineates microstructural changes in the trigeminal nerve after focal radiosurgery for trigeminal neuralgia

Purpose

Focal radiosurgery is a common treatment modality for trigeminal neuralgia (TN), a neuropathic facial pain condition. Assessment of treatment effectiveness is primarily clinical, given the paucity of investigational tools to assess trigeminal nerve changes. Since diffusion tensor imaging (DTI) provides information on white matter microstructure, we explored the feasibility of trigeminal nerve tractography and assessment of DTI parameters to study microstructural changes after treatment. We hypothesized that trigeminal tractography provides more information than 2D-MR imaging, allowing detection of unique, focal changes in the target area after radiosurgery. Changes in specific diffusivities may provide insight into the mechanism of action of radiosurgery on the trigeminal nerve.

Methods and Materials

Five TN patients (4 females, 1 male, average age 67 years) treated with Gamma Knife radiosurgery, 80 Gy/100% isodose line underwent 3Tesla MR trigeminal nerve tractography before and sequentially up to fourteen months after treatment. Fractional anisotropy (FA), radial (RD) and axial (AD) diffusivities were calculated for the radiosurgical target area defined as the region-of-interest. Areas outside target and the contralateral nerve served as controls.

Results

Trigeminal tractography accurately detected the radiosurgical target. Radiosurgery resulted in 47% drop in FA values at the target with no significant change in FA outside the target, demonstrating highly focal changes after treatment. RD but not AD changed markedly, suggesting that radiosurgery primarily affects myelin. Tractography was more sensitive than conventional gadolinium-enhanced post-treatment MR, since FA changes were detected regardless of trigeminal nerve enhancement. In subjects with long term follow-up, recovery of FA/RD correlated with pain recurrence.

Conclusions

DTI parameters accurately detect the effects of focal radiosurgery on the trigeminal nerve, serving as an in vivo imaging tool to study TN. This study is a proof of principle for further assessment of DTI parameters to understand the pathophysiology of TN and treatment effects.     

Reduced Structural Connectivity between Sensorimotor and Language Areas in Rolandic Epilepsy

Introduction

Rolandic epilepsy (RE) is a childhood epilepsy with centrotemporal (rolandic) spikes, that is increasingly associated with language impairment. In this study, we tested for a white matter (connectivity) correlate, employing diffusion weighted MRI and language testing.

Methods

Twenty-three children with RE and 23 matched controls (age: 8–14 years) underwent structural (T1-weighted) and diffusion-weighted MRI (b = 1200 s/mm², 66 gradient directions) at 3T, as well as neuropsychological language testing. Combining tractography and a cortical segmentation derived from the T1-scan, the rolandic tract were reconstructed (pre- and postcentral gyri), and tract fractional anisotropy (FA) values were compared between patients and controls. Aberrant tracts were tested for correlations with language performance.

Results

Several reductions of tract FA were found in patients compared to controls, mostly in the left hemisphere; the most significant effects involved the left inferior frontal (p = 0.005) and supramarginal (p = 0.004) gyrus. In the patient group, lower tract FA values were correlated with lower language performance, among others for the connection between the left postcentral and inferior frontal gyrus (p = 0.043, R = 0.43).

Conclusion

In RE, structural connectivity is reduced for several connections involving the rolandic regions, from which the epileptiform activity originates. Most of these aberrant tracts involve the left (typically language mediating) hemisphere, notably the pars opercularis of the inferior frontal gyrus (Broca’s area) and the supramarginal gyrus (Wernicke’s area). For the former, reduced language performance for lower tract FA was found in the patients. These findings provide a first microstructural white matter correlate for language impairment in RE.     

Neuroanatomical pattern of mitochondrial complex I pathology varies between schizophrenia, bipolar disorder and major depression

Background

Mitochondrial dysfunction was reported in schizophrenia, bipolar disorderand major depression. The present study investigated whether mitochondrial complex I abnormalities show disease-specific characteristics.

Methodology/Principal Findings

mRNA and protein levels of complex I subunits NDUFV1, NDUFV2 and NADUFS1, were assessed in striatal and lateral cerebellar hemisphere postmortem specimens and analyzed together with our previous data from prefrontal and parieto-occipital cortices specimens of patients with schizophrenia, bipolar disorder, major depression and healthy subjects. A disease-specific anatomical pattern in complex I subunits alterations was found. Schizophrenia-specific reductions were observed in the prefrontal cortex and in the striatum. The depressed group showed consistent reductions in all three subunits in the cerebellum. The bipolar group, however, showed increased expression in the parieto-occipital cortex, similar to those observed in schizophrenia, and reductions in the cerebellum, yet less consistent than the depressed group.

Conclusions/Significance

These results suggest that the neuroanatomical pattern of complex I pathology parallels the diversity and similarities in clinical symptoms of these mental disorders.     

Role of basal ganglia circuits in resisting interference by distracters: a swLORETA study

Background

The selection of task-relevant information requires both the focalization of attention on the task and resistance to interference from irrelevant stimuli. Both mechanisms rely on a dorsal frontoparietal network, while focalization additionally involves a ventral frontoparietal network. The role of subcortical structures in attention is less clear, despite the fact that the striatum interacts significantly with the frontal cortex via frontostriatal loops. One means of investigating the basal ganglia''s contributions to attention is to examine the features of P300 components (i.e. amplitude, latency, and generators) in patients with basal ganglia damage (such as in Parkinson''s disease (PD), in which attention is often impaired). Three-stimulus oddball paradigms can be used to study distracter-elicited and target-elicited P300 subcomponents.

Methodology/Principal Findings

In order to compare distracter- and target-elicited P300 components, high-density (128-channel) electroencephalograms were recorded during a three-stimulus visual oddball paradigm in 15 patients with early PD and 15 matched healthy controls. For each subject, the P300 sources were localized using standardized weighted low-resolution electromagnetic tomography (swLORETA). Comparative analyses (one-sample and two-sample t-tests) were performed using SPM5® software. The swLORETA analyses showed that PD patients displayed fewer dorsolateral prefrontal (DLPF) distracter-P300 generators but no significant differences in target-elicited P300 sources; this suggests dysfunction of the DLPF cortex when the executive frontostriatal loop is disrupted by basal ganglia damage.

Conclusions/Significance

Our results suggest that the cortical attention frontoparietal networks (mainly the dorsal one) are modulated by the basal ganglia. Disruption of this network in PD impairs resistance to distracters, which results in attention disorders.     

Inhibition of striatal soluble guanylyl cyclase-cGMP signaling reverses basal ganglia dysfunction and akinesia in experimental parkinsonism

Objective

There is clearly a necessity to identify novel non-dopaminergic mechanisms as new therapeutic targets for Parkinson''s disease (PD). Among these, the soluble guanylyl cyclase (sGC)-cGMP signaling cascade is emerging as a promising candidate for second messenger-based therapies for the amelioration of PD symptoms. In the present study, we examined the utility of the selective sGC inhibitor 1H-[1], [2], [4] oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ) for reversing basal ganglia dysfunction and akinesia in animal models of PD.

Methods

The utility of the selective sGC inhibitor ODQ for reversing biochemical, electrophysiological, histochemical, and behavioral correlates of experimental PD was performed in 6-OHDA-lesioned rats and mice chronically treated with MPTP.

Results

We found that one systemic administration of ODQ is sufficient to reverse the characteristic elevations in striatal cGMP levels, striatal output neuron activity, and metabolic activity in the subthalamic nucleus observed in 6-OHDA-lesioned rats. The latter outcome was reproduced after intrastriatal infusion of ODQ. Systemic administration of ODQ was also effective in improving deficits in forelimb akinesia induced by 6-OHDA and MPTP.

Interpretation

Pharmacological inhibition of the sGC-cGMP signaling pathway is a promising non-dopaminergic treatment strategy for restoring basal ganglia dysfunction and attenuating motor symptoms associated with PD.     

Dissociable Neural Systems for Timing: Evidence from Subjects with Basal Ganglia Lesions

Background

The neural basis of timing remains poorly understood. Although controversy persists, many lines of evidence, including studies in animals, functional imaging studies in humans and lesion studies in humans and animals suggest that the basal ganglia are important for temporal processing [1].

Methodology/Principal Findings

We report data from a wide range of timing tasks from two subjects with disabling neurologic deficits caused by bilateral lesions of the basal ganglia. Both subjects perform well on tasks assessing time estimation, reproduction and production tasks. Additionally, one subject performed normally on psychophysical tasks requiring the comparison of time intervals ranging from milliseconds to seconds; the second subject performed abnormally on the psychophysical task with a 300ms standard but did well with 600ms, 2000ms and 8000ms standards. Both subjects performed poorly on an isochronous rhythm production task on which they are required to maintain rhythmic tapping.

Conclusions/Significance

As studies of subjects with brain lesions permit strong inferences regarding the necessity of brain structures, these data demonstrate that the basal ganglia are not crucial for many sub- or supra-second timing operations in humans but are needed for the timing procedures that underlie the production of movements. This dissociation suggests that distinct and dissociable processes may be employed to measure time intervals. Inconsistencies in findings regarding the neural basis of timing may reflect the availability of multiple temporal processing routines that are flexibly implemented in response to task demands.     

Brain networks for integrative rhythm formation

Background

Performance of externally paced rhythmic movements requires brain and behavioral integration of sensory stimuli with motor commands. The underlying brain mechanisms to elaborate beat-synchronized rhythm and polyrhythms that musicians readily perform may differ. Given known roles in perceiving time and repetitive movements, we hypothesized that basal ganglia and cerebellar structures would have greater activation for polyrhythms than for on-the-beat rhythms.

Methodology/Principal Findings

Using functional MRI methods, we investigated brain networks for performing rhythmic movements paced by auditory cues. Musically trained participants performed rhythmic movements at 2 and 3 Hz either at a 1∶1 on-the-beat or with a 3∶2 or a 2∶3 stimulus-movement structure. Due to their prior musical experience, participants performed the 3∶2 or 2∶3 rhythmic movements automatically. Both the isorhythmic 1∶1 and the polyrhythmic 3∶2 or 2∶3 movements yielded the expected activation in contralateral primary motor cortex and related motor areas and ipsilateral cerebellum. Direct comparison of functional MRI signals obtained during 3∶2 or 2∶3 and on-the-beat rhythms indicated activation differences bilaterally in the supplementary motor area, ipsilaterally in the supramarginal gyrus and caudate-putamen and contralaterally in the cerebellum.

Conclusions/Significance

The activated brain areas suggest the existence of an interconnected brain network specific for complex sensory-motor rhythmic integration that might have specificity for elaboration of musical abilities.     

Risky Decisions and Their Consequences: Neural Processing by Boys with Antisocial Substance Disorder

Background

Adolescents with conduct and substance problems (“Antisocial Substance Disorder” (ASD)) repeatedly engage in risky antisocial and drug-using behaviors. We hypothesized that, during processing of risky decisions and resulting rewards and punishments, brain activation would differ between abstinent ASD boys and comparison boys.

Methodology/Principal Findings

We compared 20 abstinent adolescent male patients in treatment for ASD with 20 community controls, examining rapid event-related blood-oxygen-level-dependent (BOLD) responses during functional magnetic resonance imaging. In 90 decision trials participants chose to make either a cautious response that earned one cent, or a risky response that would either gain 5 cents or lose 10 cents; odds of losing increased as the game progressed. We also examined those times when subjects experienced wins, or separately losses, from their risky choices. We contrasted decision trials against very similar comparison trials requiring no decisions, using whole-brain BOLD-response analyses of group differences, corrected for multiple comparisons. During decision-making ASD boys showed hypoactivation in numerous brain regions robustly activated by controls, including orbitofrontal and dorsolateral prefrontal cortices, anterior cingulate, basal ganglia, insula, amygdala, hippocampus, and cerebellum. While experiencing wins, ASD boys had significantly less activity than controls in anterior cingulate, temporal regions, and cerebellum, with more activity nowhere. During losses ASD boys had significantly more activity than controls in orbitofrontal cortex, dorsolateral prefrontal cortex, brain stem, and cerebellum, with less activity nowhere.

Conclusions/Significance

Adolescent boys with ASD had extensive neural hypoactivity during risky decision-making, coupled with decreased activity during reward and increased activity during loss. These neural patterns may underlie the dangerous, excessive, sustained risk-taking of such boys. The findings suggest that the dysphoria, reward insensitivity, and suppressed neural activity observed among older addicted persons also characterize youths early in the development of substance use disorders.