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OBJECTIVE Brainstem cavernous malformations (CMs) often require resection due to their aggressive natural history causing hemorrhage and progressive neurological deficits. The authors report a novel intraoperative neuromonitoring technique of direct brainstem somatosensory evoked potentials (SSEPs) for functional mapping intended to help guide surgery and subsequently prevent and minimize postoperative sensory deficits. METHODS Between 2013 and 2019 at the Stanford University Hospital, intraoperative direct brainstem stimulation of primary somatosensory pathways was attempted in 11 patients with CMs. Stimulation identified nucleus fasciculus, nucleus cuneatus, medial lemniscus, or safe corridors for incisions. SSEPs were recorded from standard scalp subdermal electrodes. Stimulation intensities required to evoke potentials ranged from 0.3 to 3.0 mA or V. RESULTS There were a total of 1 midbrain, 6 pontine, and 4 medullary CMs—all with surrounding hemorrhage. In 7/11 cases, brainstem SSEPs were recorded and reproducible. In cases 1 and 11, peripheral median nerve and posterior tibial nerve stimulations did not produce reliable SSEPs but direct brainstem stimulation did. In 4/11 cases, stimulation around the areas of hemosiderin did not evoke reliable SSEPs. The direct brainstem SSEP technique allowed the surgeon to find safe corridors to incise the brainstem and resect the lesions. CONCLUSIONS Direct stimulation of brainstem sensory structures with successful recording of scalp SSEPs is feasible at low stimulation intensities. This innovative technique can help the neurosurgeon clarify distorted anatomy, identify safer incision sites from which to evacuate clots and CMs, and may help reduce postoperative neurological deficits. The technique needs further refinement, but could potentially be useful to map other brainstem lesions.

The hot cross bun (HCB) sign encompasses a cross-shaped hyperintensity area in the pons on axial T2-weighted magnetic resonance imaging (MRI). The HCB sign is characteristic of multiple system atrophy (MSA) and has occasionally been observed in other neurological disorders. Here, we report an autopsied case of corticobasal degeneration (CBD) that showed the HCB sign. A female patient presented with progressive gait disturbance and cognitive impairment at the age of 60 years. A neurological examination revealed dysarthria, muscle rigidity of the limbs, akinesia, truncal ataxia, urinary incontinence, and dementia. The HCB sign was observed on a brain MRI at the age of 65 years, and a clinical diagnosis of possible MSA was made. She died of pneumonia at the age of 67 years. A postmortem observation, provided neuropathological findings characteristic of CBD, including the presence of astrocytic plaques, pretangles, neuropil threads, and ballooned neurons in association with four-repeat-tau aggregation. Interestingly, the pons displayed severe neuronal loss and astrogliosis that were prominent in the pontine and raphe nuclei. Myelin sheath depletion was prominent in the transverse fibers of the pontine base and the myelinated fibers of the pontine tegmentum in contrast to relative sparing of the pontine corticospinal tract and medial lemniscus. The cerebellar dentate nucleus exhibited neuronal loss and grumose degeneration. Western blot analysis of sarkosyl-insoluble fractions from brain tissue lysates using an anti-phosphorylated tau antibody identified immunoreactive signal bands in approximately 37-40, 43, 64, and 68 kDa, consistent with CBD. Genetic analysis did not reveal any known pathogenic mutations in the microtubule-associated protein tau gene (MAPT). Our case was characterized by the HCB sign and concordant neuropathological changes in the pons. CBD should be considered an underlying pathology of the HCB sign, even though the pontocerebellar changes would be unusual in CBD cases.

Context Although diabetic peripheral neuropathy (DPN) is predominantly considered a disorder of the peripheral nerves, some evidence for central nervous system involvement has recently emerged. However, whether or to what extent the microstructure of central somatosensory tracts may be injured remains unknown. Objective This work aimed to detect the microstructure of central somatosensory tracts in type 2 diabetic patients and to correlate it with the severity of DPN. Methods A case-control study at a tertiary referral hospital took place with 57 individuals with type 2 diabetes (25 with DPN, 32 without DPN) and 33 nondiabetic controls. The fractional anisotropy (FA) values of 2 major somatosensory tracts (the spinothalamic tract and its thalamocortical [spino-thalamo-cortical, STC] pathway, the medial lemniscus and its thalamocortical [medial lemnisco-thalamo-cortical, MLTC] pathway) were assessed based on diffusion tensor tractography. Regression models were further applied to detect the association of FA values with the severity of DPN in diabetic patients. Results The mean FA values of left STC and left MLTC pathways were significantly lower in patients with DPN than those without DPN and controls. Moreover, FA values of left STC and left MLTC pathways were significantly associated with the severity of DPN (expressed as Toronto Clinical Scoring System values) in patients after adjusting for multiple confounders. Conclusion Our findings demonstrated the axonal degeneration of central somatosensory tracts in type 2 diabetic patients with DPN. The parallel disease progression of the intracranial and extracranial somatosensory system merits further attention to the central nerves in diabetic patients with DPN.

ObjectiveFocused ultrasound thalamotomy is an effective treatment for tremor; however, side effects may occur. The purpose of the present study was to investigate the spatial relationship between thalamotomies and specific sensory side effects and their functional connectivity with somatosensory cortex and relationship to the medial lemniscus (ML).MethodsSensory adverse effects were categorized into 4 groups based on the location of the disturbance: face/mouth/tongue numbness/paresthesia, hand-only paresthesia, hemibody/limb paresthesia, and dysgeusia. Then, areas of significant risk (ASRs) for each category were defined using voxel-wise mass univariate analysis and overlaid on corresponding odds ratio maps. The ASR associated with the maximum risk was used as a region of interest in a normative functional connectome to determine side effect–specific functional connectivity. Finally, each ASR was overlaid on the ML derived from normative template.ResultsOf 103 patients, 17 developed sensory side effects after thalamotomy persisting 3 months after the procedures. Lesions producing sensory side effects extended posteriorly into the principle sensory nucleus of the thalamus or below the thalamus in the ML. The topography of sensory adverse effects followed the known somatotopy of the ML and the sensory nucleus. Functional connectivity patterns between each sensory-specific thalamic seed and the primary somatosensory areas supported the role of the middle insula in processing of gustatory information and in multisensory integration.ConclusionsDistinct regions in the sensory thalamus and its afferent connections rise to specific sensory disturbances. These findings demonstrate the relationship between the sensory thalamus, ML, and bilateral sensory cortical areas.

OBJECTIVEDeep brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates motor symptoms in patients with Parkinson’s disease (PD). However, the underlying mechanism of tremor suppression is not well understood. Stimulation of white matter tracts, such as the dentatorubrothalamic tract (DRT), might be involved. Also, side effects, including dysarthria, might result from (unwanted) stimulation of white matter tracts in proximity to the STN. The aim of this study was to establish an association between stimulation effect on tremor and dysarthria and stimulation location relative to relevant white matter tracts.METHODSIn 35 PD patients in whom a bilateral STN DBS system was implanted, the authors established clinical outcome measures per electrode contact. The distance from each stimulation location to the center of the DRT, corticopontocerebellar tract, pyramidal tract (PT), and medial lemniscus was determined using diffusion-weighted MRI data. Clinical outcome measures were subsequently related to the distances to the white matter tracts.RESULTSPatients with activated contacts closer to the DRT showed increased tremor improvement. Proximity of activated contacts to the PT was associated with dysarthria.CONCLUSIONSProximity to specific white matter tracts is associated with tremor outcome and side effects in DBS. This knowledge can help to optimize both electrode placement and postsurgical electrode contact selection. Presurgical white matter tract visualization may improve targeting and DBS outcome. These findings are of interest not only for treatment in PD, but potentially also for other (movement) disorders.

There are few detailed studies on the pathways through the human brainstem and even fewer on those through the pons. This thesis aims to address this lack of fine detail, and used ultra-high-field magnetic resonance imaging (MRI) of human and macaque brains to identify and characterise fibre tracts connecting cortical and spinal areas as they traverse through brainstem and thalamic structures. The material in this thesis is based on a unique dataset of ultra-high-field (7 Tesla – Duke and 11, 7 Tesla – Johns Hopkins) MRI scans on postmortem specimens, on which deterministic tractography has been applied based on high-angular-resolution diffusion imaging (HARDI) and subsequently higher order tensor glyph models. The first results section of the thesis (Chapter 3) maps the descending fibre bundles associated with movement. From the motor cortical areas, the fibres of the internal capsule are traced through the crus cerebri, basilar pons and pyramids in three dimensions to reveal their organisation into functional and topographic subdivisions. While human cortico-pontine, -bulbar and -spinal tracts were traditionally considered to be dispersed, or a “melange”, I show here a much more discrete and defined organisation of these descending fibre bundles. Nine descending fibre bundles are identified and their anatomical location and terminations are described. A hitherto unknown pathway at the midline of the pons has been discovered and named herein as the Stria Pontis which connects the neocortex to the pontine tegmentum. Ten transverse fibre bundles connecting the pontine nuclei to the cerebellum are also identified. The second results section (Chapter 4) analyses the sensory pathways; the dorsal column - medial lemniscus pathway, the spinothalamic tract, the spinal trigeminal tract and the trigeminothalamic tracts. The third results section (Chapter 5) analyses the dentato-rubro-thalamic tract. The mapping identifies the superior cerebellar peduncle, the patterning of the fibres within the superior cerebellar decussation, the patterning of the fibres within the red nucleus and finally the projection of the dentato-rubro-thalamic tract from the red nucleus to the ventral lateral nucleus of the thalamus. Finally, I characterised 117 already known anatomical parts, areas and structures of the brainstem and thalamus in 3D.

Background The pedunculopontine nucleus (PPN) has been studied as a possible target for deep brain stimulation (DBS) for Parkinson’s disease (PD). However, identifying the PPN can be challenging as the PPN is poorly visualized on conventional or even high-resolution MR scans. From histological studies it is known that the PPN is surrounded by major white matter tracts, which could function as possible anatomical landmarks. Methods This study aimed to localize the PPN using 7T magnetic resonance (MR) imaging and diffusion tensor imaging (DTI) of its white matter borders in one post-mortem brain. Histological validation of the same specimen was performed. The PPN was segmented in both spaces, after which the two masks were compared using the Dice Similarity Index (DSI). The DSI compared the similarity of two samples on an inter-individual level and validated the MR findings. The error in distance between the center of the two 3D segmentations was measured by use of the Euclidean distance. Results The PPN can be found in between the superior cerebellar peduncle and the medial lemniscus on both the FA-maps of the DTI images and the histological sections. The histological transverse sections showed to be superior to recognize the PPN (DSI: 1.0). The DTI images have a DSI of 0.82. The overlap-masks of both spaces showed a DSI of 0.32, whereas the concatenation-masks of both spaces showed a remarkable overlap, a DSI of 0.94. Euclidean distance of the overlap- and concatenation-mask in the two spaces showed to be 1.29 mm and 1.59 mm, respectively. Conclusion This study supports previous findings that the PPN can be identified using FA-maps of DTI images. For possible clinical application in DBS localization, in vivo validation of the findings of our study is needed.

SUMMARY: Oculodentodigital dysplasia, a rare genetic disorder caused by mutations in the gene encoding gap junction protein 1, classically presents with typical facial features, dental and ocular anomalies, and syndactyly. Oligosymptomatic patients are common and difficult to recognize, in particular if syndactyly is absent. Neurologic manifestation occurs in approximately 30% of patients, and leukodystrophy or T2 hypointensity of gray matter structures or both have been noted in individual patients. To investigateMRimaging changes in oculodentodigital dysplasia, we retrospectively and systematically reviewed 12 MRIs from 6 genetically confirmed patients. Diffuse supratentorial hypomyelination, T2-hypointense Rolandic and primary visual cortex, and symmetric involvement of middle cerebellar peduncle, pyramidal tract, and medial lemniscus was present in all, T2-hypointense pallidum and dentate nucleus in 2 patients each. This consistent, characteristic pattern of diffuse supratentorial hypomyelination and brain stem involvement differs from other hypomyelinating and nonhypomyelinating leukodystrophies with brain stem involvement, and its recognition should trigger genetic testing for oculodentodigital dysplasia.

We report the successful management of gait dysfunction in a patient with coordination problems using an insole with a metatarsal inhibition bar (MIB) and a deep heel cup. Furthermore, we investigated the state of the neural tracts via diffusion tensor tractography (DTT). A 23-month-old boy with gait dysfunction presented with toe walking with a wide base and decreased hip flexion. Motor weakness or spasticity was not observed. Conventional brain magnetic resonance imaging did not reveal any abnormal findings, but DTT revealed disrupted bilateral corticoreticulospinal tracts (CRTs). No abnormalities were observed in the corticospinal tract or the medial lemniscus. We applied a custom-made insole with an MIB and a deep heel cup. Immediately after application, the patient’s gait pattern stabilized significantly and was nearly normalized. Our therapeutic experience indicates that the application of an insole with an MIB and deep heel cups could be beneficial for patients with coordination problems and gait dysfunction. Our DTT results showed that CRTs could be the causative brain pathology for gait dysfunction in patients with coordination problems.