Neuroimaging to Facilitate Clinical Trials in Huntington's Disease: Current Opinion from the EHDN Imaging Working Group.

 Neuroimaging is increasingly being included in clinical trials of Huntington's disease (HD) for a wide range of purposes from participant selection and safety monitoring, through to demonstration of disease modification. Selection of the appropriate modality and associated analysis tools requires careful consideration. On behalf of the EHDN Imaging Working Group, we present current opinion on the utility and future prospects for inclusion of neuroimaging in HD trials. Covering the key imaging modalities of structural-, functional- and diffusion- MRI, perfusion imaging, positron emission tomography, magnetic resonance spectroscopy, and magnetoencephalography, we address how neuroimaging can be used in HD trials to: 1) Aid patient selection, enrichment, stratification, and safety monitoring; 2) Demonstrate biodistribution, target engagement, and pharmacodynamics; 3) Provide evidence for disease modification; and 4) Understand brain re-organization following therapy. We also present the challenges of translating research methodology into clinical trial settings, including equipment requirements and cost, standardization of acquisition and analysis, patient burden and invasiveness, and interpretation of results. We conclude, that with appropriate consideration of modality, study design and analysis, imaging has huge potential to facilitate effective clinical trials in HD.

In vivo neurochemistry of primary focal hand dystonia: a magnetic resonance spectroscopic neurometabolite profiling study at 3T.

The neurochemical basis of dystonia is unknown. The purpose of this study was to assess the differences of the inhibitory neurotransmitter, gamma amino butyric acid (GABA), in the sensorimotor cortex and the basal ganglia using magnetic resonance spectroscopy with optimized GABA sensitivity. Twenty-two patients with focal hand dystonia and 22 healthy controls were studied. No significant differences in GABA were observed between the groups in either the sensorimotor cortex or in the basal ganglia.

Selective hyposmia in Parkinson disease: association with hippocampal dopamine activity.

Olfactory dysfunction is common in patients with Parkinson disease (PD) and has been attributed to early pathological deposition of Lewy bodies and Lewy neurites in primary olfactory centers. However, olfactory deficits do not always worsen over time despite progression of disease raising the possibility of additional pathobiological mechanisms contributing to olfactory functions in PD, such as changes in olfactory neurotransmitter functions. Neurotransmitter changes, such as altered dopaminergic status, may also better explain the selective nature of odor identification deficits in PD. Proper odor identification depends on higher order structures, such as the hippocampus, for olfactory cognitive or memory processing. Using the University of Pennsylvania Smell Identification Test (UPSIT), we previously identified three odors (banana, licorice, dill pickle, labeled as UPSIT-3) that PD subjects most frequently failed to recognize compared to age- and gender-matched controls. We also identified six odors that were equally successfully identified by controls and PD subjects (NPD-Olf6). A ratio of UPSIT-3 divided by NPD-Olf6 scores provides another descriptor of selective hyposmia in PD ("olfactory ratio"). In this study we investigated the pathophysiology of hyposmia in PD using dopamine transporter (DAT) PET. Twenty-nine PD patients (Hoehn and Yahr stages I-III; 7f/22m; age 60.2+/-10.8) underwent olfactory testing using the UPSIT and [(11)C]beta-CFT DAT PET. DAT binding potentials (BP) were assessed in the hippocampus, amygdala, ventral and dorsal striatum. We found that correlation coefficients between total UPSIT scores and regional brain DAT BP were highest for the hippocampus (Rs=0.54, P=0.002) and lower for the amygdala (Rs=0.44, P=0.02), ventral (Rs=0.48, P=0.008) and dorsal striatum (Rs=0.39, P=0.03). Correlations were most significant for the selective hyposmia measures and hippocampal DAT: UPSIT-3 (Rs=0.65, P=0.0001) and the olfactory ratio (Rs=0.74, P<0.0001). We conclude that selective hyposmia in PD is more robustly correlated with hippocampal rather than amygdala, ventral or dorsal striatal dopamine innervation as shown by DAT binding. These findings indicate that mesolimbic dopamine innervation of the hippocampus may be a determinant of selective hyposmia in PD.

Loss of inhibition in sensorimotor networks in focal hand dystonia.

OBJECTIVE: To investigate GABA-ergic receptor density and associated brain functional and grey matter changes in focal hand dystonia (FHD). METHODS: 18 patients with FHD of the right hand and 18 age and gender matched healthy volunteers (HV) participated in this study. We measured the density of GABA-A receptors using [11C] Flumazenil and perfusion using [15O] H2O. Anatomical images were also used to measure grey matter volume with voxel-based morphometry (VBM). RESULTS: In FHD patients compared to HV, the vermis VI of the right cerebellum and the left sensorimotor cortex had a decrease of Flumazenil binding potential (FMZ-BP), whereas the striatum and the lateral cerebellum did not show significant change. Bilateral inferior prefrontal cortex had increased FMZ-BP and an increase of perfusion, which correlated negatively with disease duration. Only the left sensorimotor cortex showed a decrease of grey matter volume. INTERPRETATION: Impairments of GABAergic neurotransmission in the cerebellum and the sensorimotor cortical areas could explain different aspects of loss of inhibitory control in FHD, the former being involved in maladaptive plasticity, the latter in surround inhibition. Reorganization of the inferior prefrontal cortices, part of the associative network, might be compensatory for the loss of inhibitory control in sensorimotor circuits. These findings suggest that cerebellar and cerebral GABAergic abnormalities could play a role in the functional imbalance of striato-cerebello-cortical loops in dystonia.

Psychosis in Parkinson's disease: From the soft signs to the hard science.

Patients with Parkinson's disease (PD) may develop a wide spectrum of non-motor symptoms during the course of illness. Psychosis is one such commonly observed non-motor symptoms of PD. Although several studies based on neuroimaging, genetics, retinal imaging, and neuropsychological evaluations have explored the pathogenesis of psychosis in PD; exact neural correlates are yet to be understood. Identification of factors related to psychosis in PD is important, as psychosis has been reported to be associated with higher rates of mortality, caregiver distress, and nursing home placements. This review highlights the potential of the previous studies to gain further insights into the soft signs and hard science related to psychosis in PD. Studies based on neuropsychological evaluations have revealed significant dysfunction in attention, executive and visuospatial functions in patients with PD and psychosis. Neuroimaging studies reveal grey matter atrophy in regions of the brain corresponding to both dorsal and ventral visual pathways, hippocampus, and cholinergic structures. Meanwhile, functional imaging studies suggest existence of an aberrant top-to-bottom visual processing system, which dominates the normal bottom-to-top system in patients with PD and visual hallucinations. Although nucleotide polymorphisms of several genes have been studied in PD patients with psychosis, those on -45C>T polymorphisms of cholecystokinin gene (CCK) have shown the greatest promise because of its association with psychosis in PD. All these taken together, cohesively unfold the current status of research in patients with PD and psychosis. This paper also highlights the missing links and discusses the approach to future research in this field.

Modulation of intrinsic resting-state fMRI networks in women with chronic migraine.

OBJECTIVE: To evaluate the intrinsic resting functional connectivity of the default mode network (DMN), salience network (SN), and central executive network (CEN) network in women with chronic migraine (CM), and whether clinical features are associated with such abnormalities. METHODS: We analyzed resting-state connectivity in 29 women with CM as compared to age- and sex-matched controls. Relationships between clinical characteristics and changes in targeted networks connectivity were evaluated using a multivariate linear regression model. RESULTS: All 3 major intrinsic brain networks were less coherent in CM (DMN: p = 0.030, SN: p = 0.007, CEN: p = 0.002) as compared to controls. When stratified based on medication overuse headache (MOH) status, CM without MOH (DMN: p = 0.029, SN: p = 0.023, CEN: p = 0.003) and CM with MOH (DMN: p = 0.016, SN: p = 0.016, CEN: p = 0.015) were also less coherent as compared to controls. There was no difference in CM with MOH as compared to CM without MOH (DMN: p = 0.382, SN: p = 0.408, CEN: p = 0.419). The frequency of moderate and severe headache days was associated with decreased connectivity in SN (p = 0.003) and CEN (p = 0.015), while cutaneous allodynia was associated with increased connectivity in SN (p = 0.011). CONCLUSIONS: Our results demonstrated decreased overall resting-state functional connectivity of the 3 major intrinsic brain networks in women with CM, and these patterns were associated with frequency of moderate to severe headache and cutaneous allodynia.

Cortical Substrate of Supraspinal Fatigue following Exhaustive Aerobic Exercise Localizes to a Large Cluster in the Anterior Premotor Cortex.

Strenuous exercise leads to a progressive reduction in the performance of voluntary physical exercise. This is due to a process described as fatigue and is defined as the failure to maintain the required or expected power output. While some of this is muscular in origin, there are data suggestive of how fatigue is modulated by cortical signals, leading to a concept of central fatigue. The previously reported fatigue-induced changes in cortical activity may have been due to blood oxygen-dependent (BOLD) signal drift and/or neural habituation alone. We implemented a functional magnetic resonance imaging paradigm to effectively isolate brain areas responsible for central (supraspinal) fatigue following exercise. Our data identify a large cluster that includes dominant the anterior ventral premotor cortex (aPMv), the insula and postcentral gyrus as critical nodes in the brain network where supraspinal fatigue might have their functional neural imprints. Findings here show that activity in the ipsilateral aPMv and the adjacent areas in the premotor cortex correlates with both localized fatigue (fatigue specific hand grip contraction), and generalized full body exhaustive fatigue. In addition, from a methodological standpoint, we have also shown that the effects of BOLD signal drift can be modeled and removed to arrive at specific brain activity patterns in our experiments. Once the loci of central fatigue are isolated in this way, treatments aimed at modulating activity in these premotor areas may reduce exercise-induced fatigue and perhaps also benefit various clinical conditions in which fatigue is a major symptom.

Duration of disease does not equally influence all aspects of quality of life in Parkinson's disease.

Health related quality of life (HRQoL) is negatively impacted in patients suffering from Parkinson's disease (PD). For the specific components that comprise HRQoL, the relationship between clinical variables, such as disease duration, is not fully characterized. In this cross-sectional study (n=302), self-reported HRQoL on the Parkinson's Disease Questionnaire (PDQ-39) was evaluated as a global construct as well as individual subscale scores. HRQoL was compared in three groups: those within 5years of diagnosis, those within 6-10years of diagnosis, and those greater than 11years since diagnosis. Non-parametric analyses revealed lower HRQoL with increasing disease duration when assessed as a global construct. However, when subscales were evaluated, difficulties with bodily discomfort and cognitive complaints were comparable in individuals in the 1-5years and 6-10year duration groups. Exploratory regression analyses suggested disease duration does explain unique variance in some subscales, even after controlling for Hoehn and Yahr stage and neuropsychiatric features. Our findings show that HRQoL domains in PD patients are affected differentially across the duration of the disease. Clinicians and researchers may need to tailor interventions intended to improve HRQoL at different domains as the disease progresses.

Somatotopy and attentional modulation of the human parietal and opercular regions.

The somatotopical organization of the postcentral gyrus is well known, but less is known about the somatotopical organization of area 2, the somatosensory association areas in the postparietal cortex, and the parietal operculum. The extent to which these areas are modulated by attention is also poorly understood. For these reasons, we measured the BOLD signal when rectangular parallelepipeds of varying shape were presented to the immobile right hand or right foot of 10 subjects either discriminating these or just being stimulated. Activation areas in each subject were mapped against cytoarchitectural probability maps of area 2, IP1, and IP2 along the intraparietal sulcus and the parietal opercular areas OP1-OP4. In area 2, the somatotopical representation of the hand and foot were distinctly separate, whereas there was considerable overlap in IP1 and no clear evidence of separate representations in OP1, OP4, and IP2. The overlap of hand and foot representations increased in the following order: area 3a, 3b, 1, 2, IP1, OP4, IP2, and OP1. There were significant foot representations but no hand representations in right (ipsilateral) areas 3a, 3b, and 1. Shape discrimination using the foot as opposed to stimulation enhanced the signal in OP4 bilaterally, whereas discrimination with the hand enhanced the signal bilaterally in area 2, IP1, and IP2. These results indicate that somatosensory areas in humans are arranged from strong somatotopy into no somatotopy in the following order: 3a, 3b, 1, 2, IP1, OP4, IP2, and OP1. Higher order areas such as IP1, IP2, and OP4 showed task-related attentional enhancement.

Medically unexplained neurologic symptoms: a primer for physicians who make the initial encounter.

Medically unexplained symptoms are ubiquitous in clinical practice. Medical use costs of medically unexplained symptoms are projected at approximately $256 billion per year. When initially seen, these symptoms are often baffling, not only to the patients but also to the physicians who encounter them. Because of this, properly diagnosing them is seen generally as difficult at best, leading to massive overuse of unnecessary testing. Subsequently, their management can be cumbersome. All this burdens the patients with unnecessary costs, financially and emotionally. This primer discusses historical perspectives of these and the changing nomenclature, and outlines how to think about these complex symptoms and neurologic findings that will enable a positive diagnosis rather than a diagnosis of exclusion. We also offer useful heuristic principles of their management so that physician-patient relationships can be better maintained and the quality of life of these patients can be improved by way of some simple, economic approaches.

Two mechanisms of protracted reaction times mediated by dissociable cortical networks.

When people divide attention between two sensory modalities and respond rapidly to stimuli in either modality, the reaction times (RTs) are longer than when they selectively attend and respond to one sensory modality. There is a further increase in RT when subjects use different fingers to respond to stimuli from different modalities as compared to when they use the same finger for both modalities. Here we use functional magnetic resonance imaging to show that division of attention bilaterally activates the caudal prefrontal areas near the precentral sulcus and areas in the intraparietal sulcus. All RT tasks, whether different fingers for different modalities or one finger for both modalities was used, activated identical motor areas 4a, 4p, supplementary and cingulate, the basal ganglia and the ventral anterior thalami. The increased blood oxygen level-dependent signal from motor cortical areas was anatomically distinct from the prefrontal/parietal areas. These anatomically dissociable neural substrates of division of attention and motor control may be responsible for the different types of RT delays that we have found. In the brain, there were no differences in the BOLD signal irrespective of whether the effector was specified a priori or was specified only after the sensory signal was received.

Somatosensory areas engaged during discrimination of steady pressure, spring strength, and kinesthesia.

The aim of this study was to locate neuronal populations in the somatosensory areas engaged during discrimination of differences in: (1) static sustained pressure on the distal phalanx (PRESS); (2) spring strengths (SSTIFF) during active flexion of the right index finger; and (3) the change in position of a limb with contracting muscles, i.e., kinesthesia (KIN), during active flexion of the right index finger. The stimuli used were spring-loaded cylinders. The regional cerebral blood flow (rCBF) was measured with positron emission tomography (PET). The active fields were related to cytoarchitectonic areas of the somatosensory cortex (areas 3a, 3b, 1, and 2) and the primary motor cortex (areas 4a and 4p). We hypothesized that SSTIFF and KIN would activate areas 3a and 2. All three conditions, when contrasted against a rest condition, activated cytoarchitectural areas 3b, 1, and 2, and presumptive somatosensory areas in the left parietal operculum and right supramarginal gyrus in accordance with these areas receiving information from cutaneous mechanoreceptive afferents. Area 3a was only activated in SSTIFF and KIN, consistent with observations in monkeys and cats, showing that afferents from muscle receptors project to area 3a, and indicating that a similar arrangement seems to be apparent in humans. SSTIFF and KIN activated the right anterior lobe of the cerebellum, the left area 4a and left area 2 more than did PRESS, likely due to a combination of active movements and muscle receptor feed-back.