Central Nervous System Volume Research Articles

Communicating the relevance of neurodegeneration and brain atrophy to multiple sclerosis patients: patient, provider and researcher perspectives.

Central nervous system (CNS) atrophy provides valuable additional evidence of an ongoing neurodegeneration independent of lesion accrual in persons with multiple sclerosis (PwMS). However, there are limitations for interpretation of CNS volume changes at individual patient-level. Patients are receiving information on the topic of atrophy through various sources, including media, patient support groups and conferences, and discussions with their providers. Whether or not the topic of CNS atrophy should be proactively discussed with PwMS during office appointments is currently controversial. This commentary/perspective article represents perspectives of PwMS, providers and researchers with recommendations for minimizing confusion and anxiety, and facilitating proactive discussion about brain atrophy, as an upcoming routine measure in evaluating disease progression and treatment response monitoring. The following recommendations were created based on application of patient's and provider's surveys, and various workshops held over a period of 2years: (1) PwMS should receive basic information on understanding of brain functional anatomy, and explanation of inflammation and neurodegeneration; (2) the expertise for atrophy measurements should be characterized as evolving; (3) quality patient education materials on these topics should be provided; (4) the need for standardization of MRI exams has to be explained and communicated; (5) providers should discuss background on volumetric changes, including references to normal aging; (6) the limitations of brain volume assessments at an individual-level should be explained; (7) the timing and language used to convey this information should be individualized based on the patient's background and disease status; (8) a discussion guide may be a very helpful resource for use by providers/staff to support these discussions; (9) understanding the role of brain atrophy and other MRI metrics may elicit greater patient satisfaction and acceptance of the value of therapies that have proven efficacy around these outcomes; (10) the areas that represent possibilities for positive self-management of MS symptoms that foster hope for improvement should be emphasized, and in particular regarding use of physical and mental exercise that build or maintain brain reserve through increased network efficiency, and (11) an additional time during clinical visits should be allotted to discuss these topics, including creation of specific educational programs.

The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration.

Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and target RNA reduction throughout the CNS in neurons, oligodendrocytes, astrocytes and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.

Selective hippocampal subfield volume reductions in classic trigeminal neuralgia.

Trigeminal Neuralgia (TN) is a chronic neuropathic pain syndrome characterized by paroxysmal unilateral shock-like pains in the trigeminal territory most frequently attributed to neurovascular compression of the trigeminal nerve at its root entry zone. Recent advances in the study of TN suggest a possible central nervous system (CNS) role in modulation and maintenance of pain. TN and other chronic pain patients commonly experience alterations in cognition and affect, as well as abnormalities in CNS volume and microstructure in regions associated with pain perception, emotional modulation, and memory consolidation. However, the microstructural changes in the hippocampus, an important structure within the limbic system, have not been previously studied in TN patients. Here, we use grey matter analysis to assess whether TN pain is associated with altered hippocampal subfield volume in patients with classic TN. Anatomical magnetic resonance (MR) images of twenty-two right-sided TN patients and matched healthy controls underwent automated segmentation of hippocampal subfields using FreeSurfer v6.0. Right-sided TN patients had significant volumetric reductions in ipsilateral cornu ammois 1 (CA1), CA4, dentate gyrus, molecular layer, and hippocampus-amygdala transition area – resulting in decreased whole ipsilateral hippocampal volume, compared to healthy controls. Overall, we demonstrate selective hippocampal subfield volume reduction in patients with classic TN. These changes occur in subfields implicated as neural circuits for chronic pain processing. Selective subfield volume reduction suggests aberrant processes and circuitry reorganization, which may contribute to development and/or maintenance of TN symptoms.

Future Brain and Spinal Cord Volumetric Imaging in the Clinic for Monitoring Treatment Response in MS.

Volumetric analysis of brain imaging has emerged as a standard approach used in clinical research, e.g., in the field of multiple sclerosis (MS), but its application in individual disease course monitoring is still hampered by biological and technical limitations. This review summarizes novel developments in volumetric imaging on the road towards clinical application to eventually monitor treatment response in patients with MS. In addition to the assessment of whole-brain volume changes, recent work was focused on the volumetry of specific compartments and substructures of the central nervous system (CNS) in MS. This included volumetric imaging of the deep brain structures and of the spinal cord white and gray matter. Volume changes of the latter indeed independently correlate with clinical outcome measures especially in progressive MS. Ultrahigh field MRI and quantitative MRI added to this trend by providing a better visualization of small compartments on highly resolving MR images as well as microstructural information. New developments in volumetric imaging have the potential to improve sensitivity as well as specificity in detecting and hence monitoring disease-related CNS volume changes in MS.

MO‐D‐220‐08: Quantitative Embryonic Central Nervous System Imaging Using High‐ Frequency Annular Arrays

Purpose: The central nervous system (CNS) is the first organ to develop during mammalian embryogenesis and the CNS dynamically evolves well into the postnatal stages. Abnormal CNS phenotypes are normally visualized in vivo or with fixed samples using magnetic resonance imaging (MRI). Current MRI coil technology does not permit early‐stage in vivo imaging of the mouse embryo CNS. Here, a custom‐made, high‐frequency‐ultrasound annular‐array system operating at 38 MHz was utilized to perform in vivo imaging of early‐stage mouse embryo CNS. Methods: A custom‐made ultrasound scanning system using a piezopolymer‐based annular array was utilized for the imaging studies. The array had five equal‐area elements, a 6 mm total aperture, and a 12 mm geometric focus. The scanning system was designed to perform five scans across an object in order to acquire all transmit‐to‐receive data (25 data sets). This data was then synthetically focused to achieve enhanced depth of field and lateral resolution. In addition, the system utilized a coded‐excitation scheme to enhance SNR and penetration depth, and a respiratory gate to reduce motion artifacts. A full 3D volumetric data set could be acquired in approximately 2 minutes. Results: In vivo, in utero volumetric data were acquired from 78 mouse embryos spanning embryonic days 10 to 13. The data sets were processed with a semi‐automated image segmentation algorithm and brain volumes were calculated. The results indicated that during these mid‐gestational stages, there was an increase in CNS volume of 38% while volumetric renderings revealed the complex remodeling of the neuroarchitecture showing more cell proliferation than increase in brain mass. Conclusions: High‐frequency annular arrays with coded excitation offer an effective means of acquiring in vivo, in utero ultrasound data of the embryonic mouse and can be used to rapidly analyze the normal or abnormal development of the CNS during longitudinal studies.This research was supported by the National Institutes of Health (EB008606).

In vivo volumetric imaging of the mouse embryonic brain using chirp-coded excitation and a high-frequency annular-array.

Many genetically engineered mice display abnormal development of the central nervous system (CNS) and high-frequency ultrasound (HFU) offers great potential for efficient, serial in vivo phenotyping of the developing embryonic mouse brain. However, HFU mouse-embryo imaging remains challenging because of the orientation of the embryos and of the limited acoustic penetration depth of HFU. In this study, a 34-MHz, five-element annular array was excited using conventional mono-cycle and chirp-coded excitations. Synthetic focusing and pulse compression (for the chirp excitation) were used to form images with increased depth of field and penetration depth (for the chirp excitation). In utero, in vivo 3-D data sets were acquired from 48 embryos over four stages from embryonic days E10.5 to E13.5, and CNS volume renderings were obtained. The chirp-based renderings were more morphologically accurate than the mono-cycle-based renderings, and the chirp provided sufficient penetration depth to correctly segment the brain ventricles lying deep inside the mother. The chirp renderings indicated that the early CNS architecture was dominated by the third and fourth brain ventricles, with the lateral ventricles contributing more at later stages. [Work supported by NIH Grant nos. NS038461 and EB008606.]

A unifying hypothesis for hydrocephalus, Chiari malformation, syringomyelia, anencephaly and spina bifida

This work is a modified version of the Casey Holter Memorial prize essay presented to the Society for Research into Hydrocephalus and Spina Bifida, June 29th 2007, Heidelberg, Germany. It describes the origin and consequences of the Chiari malformation, and proposes that hydrocephalus is caused by inadequate central nervous system (CNS) venous drainage. A new hypothesis regarding the pathogenesis, anencephaly and spina bifida is described.Any volume increase in the central nervous system can increase venous pressure. This occurs because veins are compressible and a CNS volume increase may result in reduced venous blood flow. This has the potential to cause progressive increase in cerebrospinal fluid (CSF) volume. Venous insufficiency may be caused by any disease that reduces space for venous volume. The flow of CSF has a beneficial effect on venous drainage. In health it moderates central nervous system pressure by moving between the head and spine. Conversely, obstruction to CSF flow causes localised pressure increases, which have an adverse effect on venous drainage.The Chiari malformation is associated with hindbrain herniation, which may be caused by low spinal pressure relative to cranial pressure. In these instances, there are hindbrain-related symptoms caused by cerebellar and brainstem compression. When spinal injury occurs as a result of a Chiari malformation, the primary pathology is posterior fossa hypoplasia, resulting in raised spinal pressure. The small posterior fossa prevents the flow of CSF from the spine to the head as blood enters the central nervous system during movement. Consequently, intermittent increases in spinal pressure caused by movement, result in injury to the spinal cord. It is proposed that posterior fossa hypoplasia, which has origins in fetal life, causes syringomyelia after birth and leads to damage to the spinal cord in spina bifida. It is proposed that hydrocephalus may occur as a result of posterior fossa hypoplasia, where raised pressure occurs as a result of obstruction to flow of CSF from the head to the spine, and cerebral injury with raised pressure occurs in anencephaly by this mechanism.The current view of dysraphism is that low central nervous system pressure and exposure to amniotic fluid, damage the central nervous system. The hypothesis proposed in this essay supports the view that spina bifida is a manifestation of progressive hydrocephalus in the fetus. It is proposed that that mesodermal growth insufficiency influences both neural tube closure and central nervous system pressure, leading to dysraphism.

The venous hypothesis of hydrocephalus

Pressure in the central nervous system (CNS) depends upon the volume of tissue that it contains. This includes blood, cerebrospinal fluid (CSF), nerves and any space occupying lesions. The dependency of pressure on volume arises because the CNS is confined by bone. Venous and CSF pressure is linked to overall pressure. Arterial pressure can increase in response to overall pressure to maintain arterial supply. Continuous arterial supply can be maintained because venous blood flows out of the CNS. Reduced volumes of arterial blood will enter the system if venous outflow is interrupted. Increase in CNS volume, as occurs with space occupying lesions, causes compression of veins. This may result in increased venous pressure and reduction in flow of blood out of the CNS. Cerebrospinal fluid (CSF) is extracellular fluid; its absorption back into the circulation is influenced by venous pressure. Any increased in CNS tissue volumes can therefore lead to CSF accumulation. This may then exacerbate the hydrocephalus by further increasing overall CNS volume. Free flow of CSF around the CNS facilitates venous drainage. Blockages to CSF flow can act like space occupying lesions. Chiari malformations, where the cerebellar tonsils obstruct the foramen magnum lead to reductions in CSF flow that can occur intermittently. This leads to impairment of venous drainage which may result in accumulation of CSF. The head or the spine can be affected together or separately. The manifestation of excess fluid accumulation is hydrocephalus and syringomyelia. The speed and origin of venous insufficiency influences the morphology of individual cases particularly with regard to lateral ventricle size. When pressure increases rapidly there may be little time for CSF accumulation. Oedema, compression of intracranial CSF spaces and cerebral ischaemia follows. When venous pressure is only slightly elevated CSF will accumulate and the manifestations of ischaemia may be less apparent, although ischaemia will be a feature of all instances of pathologically raised CNS pressure.