Patients with movement disorders treated by deep brain stimulation do not always achieve successful therapeutic alleviation of motor symptoms, even in cases where surgery is without complications. Magnetic resonance imaging (MRI) offers methods to investigate structural brain-related factors that may be predictive of clinical motor outcomes. This review aimed to identify features which have been associated with variability in clinical post-operative motor outcomes in patients with Parkinson’s disease, dystonia, and essential tremor from structural MRI modalities. We performed a literature search for articles published between 1 January 2000 and 1 April 2022 and identified 5197 articles. Following screening through our inclusion criteria, we identified 60 total studies . The review captured a range of structural MRI methods and analysis techniques used to identify factors related to clinical post-operative motor outcomes from deep brain stimulation. Morphometric markers, including volume and cortical thickness were commonly identified in studies focused on patients with Parkinson’s disease and dystonia syndromes. Reduced metrics in basal ganglia, sensorimotor and frontal regions showed frequent associations with reduced motor outcomes. Increased structural connectivity to subcortical nuclei, sensorimotor and frontal regions was also associated with greater motor outcomes. In patients with tremor, increased structural connectivity to the cerebellum and cortical motor regions showed high prevalence across studies for greater clinical motor outcomes. In addition, we highlight conceptual issues for studies assessing clinical response with structural MRI and discuss future approaches towards optimizing individualized therapeutic benefits. Although quantitative MRI markers are in their infancy for clinical purposes in movement disorder treatments, structural features obtained from MRI offer the powerful potential to identify candidates who are more likely to benefit from deep brain stimulation and provide insight into the complexity of disorder pathophysiology. et al. conducted a systematic search into the studies utilizing structural MRI in association with or prediction of motor outcomes from deep brain stimulation in Parkinson’s disease, dystonia and tremor. Morphometric and diffusion-based approaches were identified as the most popular techniques, providing insight into localized and network-based changes across disorders.Andrews   DBS has become the therapeutic option of choice for Parkinson’s disease, dystonia syndromes and essential tremor if pharmacological treatments fail to provide satisfactory therapeutic relief or induce significant unwanted side effects.9 Together, these sequences can characterize pre-and post-operative structural brain-related information which can be related to changes in clinical motor symptom scores.Mediating factors of motor outcomes that are unrelated to the neurosurgical procedure have been explored. Information derivable from routine imaging for DBS screening, pre-operative stereotactic planning, and follow-up assessment present avenues to explore factors associated with motor outcome variability. Pre-operative T1- and T2-weighted structural magnetic resonance imaging (MRI) and post-operative MRI-computed tomography (CT) fusion are acquired for each patient as standard. Additional sequences that have been predominantly constrained to research applications are being increasingly incorporated into centres’ imaging routines. One modality is diffusion-weighted MRI (dMRI) which can provide clinical utility by aiding electrode implantation accuracy in relation to white matter tract bundles.10 Identifying individualized prognostic markers may provide Identifying brain-related features or biomarkers for DBS motor outcomes is crucial for several reasons. Most importantly, determining patient-specific outcome-related factors will inform the optimization of therapeutic benefits and reduce potential surgery-related side effects.11‐14 Crucially, however, functional MRI is not globally acquired as part of routine imaging protocols for DBS. Therefore, this review sought to exclude these studies and focus on techniques that are currently embedded into the clinical evaluation pathway for patients undergoing DBS surgery. Studies focusing on efficacy comparisons of DBS targets were excluded given the lack of focus on structural MRI application and existing comprehensive literature.15‐17 Additionally, quantification of stimulation overlap or measurement of contacts relative to the defined neurosurgical target were excluded, given that accuracy is indicative of successful treatment and is reviewed elsewhere.18‐20This study aimed to review the literature surrounding the use of structural MRI to identify features that have been used to account for variability in motor outcomes following DBS. Importantly, other imaging domains such as functional MRI, used to measure regional haemodynamic brain changes, have also shown efficacy to provide markers for motor outcomes.22 PubMed, Scopus, and Web of Science electronic databases were used to identify relevant literature. Article searches were restricted to full texts, written in English with a date of publication between 1 January 2000 and 1 April 2022. Database search terms are included as This review was conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement.To identify candidate articles and discount topics of non-interest, titles were scanned by the primary author. Following initial selection, the resultant articles were subject to abstract and full-text review, based on inclusion criteria . All stuTo summarize the studies included in the final selection, information was recorded by L.A. Author(s), publication date, patient sample size included in the imaging analyses, structural MRI data and analysis method, motor outcome scale, motor follow-up period and main findings were recorded for each study.The search yielded a total of 5197 and 3821 articles pre-and-post de-duplication, respectively. Following title screening, 130 articles underwent full-text review using the inclusion criteria. A total of 54 articles were extracted from the search to be included in the systematic review. Six additional articles were extracted from additional sources. Herein, 60 studies were included in the final review .72‐82 Information regarding authors, study sample sizes (n), movement disorder diagnosis, targeted DBS region, main structural MRI technique utilized (MRI), clinical scale, post-operative follow-up period(s) and summarized main findings are presented as supplementary material ; 279 patients were diagnosed with dystonia syndromes ; 230 patients were diagnosed with essential tremor.83 observed in 30 studies.50‐59 The Movement Disorder Society-Sponsored Revision of the UPDRS (MDS-UPDRS III)84 was used in eight studies.61 The gait and falls questionnaire (GFQ), freezing of gait questionnaire (FoGQ) and a stepping-in-place task (SIP), were used to assess axial symptoms in patients with Parkinson’s disease.57 For generalized, focal, segmental dystonia and X-linked dystonia-Parkinsonism, the Burke–Fahn–Marsden dystonia rating scale (BFMDRS)85 was administered in eight studies.68‐71 In addition, the unified dystonia rating scale (UDRS)86 was administered for generalized dystonia in one study.66 For cervical dystonia, the Toronto Western spasmodic torticollis rating scale (TWSTRS)87 was administered in three studies.67 For tremor, the Fahn–Tolosa–Marin (FTM) clinical rating scale for tremor88 was used in nine studies.82 In two studies, clinical testing for motor symptoms was not assessed using standardized clinical scales.81A total of nine scales used for measuring motor outcome improvement following DBS were identified in this study. Clinical scales used to measure cardinal symptoms of Parkinson’s disease including the unified Parkinson’s disease rating scale (UPDRS III)64 DBS side effects53 and contacts connected to a defined number of regions of interest.54 Details can be found in The process to determine group-based clinical post-operative motor improvements were not standardized across studies. The most common approach was to dichotomize patient groups using cut-off thresholds of clinical improvements pre-and-post DBS surgery. These thresholds are summarized in Several MRI methods and analysis techniques were identified from the 60 included studies and could be broadly characterized based on a focus on brain morphometry, iron-related features and dMRI approaches.64The most rudimentary approach identified in the review was manual image inspection for features associated with pathology. A total of three studies quantified image features in a manual fashion.71 A total of 17 studies utilized fully automated approaches to segment and process images for morphometric quantification. Seven studies adopted a voxel-based morphometry approach which is a fully automated technique used to identify voxel-wise changes of grey and white matter between groups , an open-source, widely adopted automated pipeline, for automatic segmentation, reconstruction and parcellation of structural MRI, used in eight of the studies  58 and Zero-Download Ambassador picture archiving and communication system software .34In-house medical imaging software was used in two studies. Namely, NeuroQuant  in vivo.101dMRI was the most common approach, identified in 37 studies.ed axons .99,100 D81 which models a single orientation of voxel-wise diffusion using a tensor  per voxel.97 The fundamental issue with tensor models is that given the minute scale of estimated fibres (∼0.16 to 9 μm) relative to typical voxel sizes (∼1 to 3 mm3), orientations are seldom coherent, and so single-direction tensors are an oversimplified model of the local microstructural geometrical organization.104 Furthermore, due to measurement noise and orientation complexity in dMRI, uncertainty is not accounted for in deterministic approaches.The simplest approach to tractography identified in this review was deterministic diffusion tensor imaging (DTI),a tensor .102,103 https://fsl.fmrib.ox.ac.uk/fsl; 98 Multi-fibre modelling was combined with probabilistic tractography in 13 studies.80 Probabilistic tractography quantifies the probability of each voxel being intersected from seed over successive sampling runs.105 Areas of uncertainty are reflected by voxels with corresponding low probabilities and thus, reflect confidence bounds around the most probable connections. Probabilistic multi-fibre approaches offer a more conservative approach when modelling non-dominant connectivity pathways.97Multi-fibre modelling is used to better estimate multiple diffusion directions, and thus, better represent the complex geometrical organization of fibres in each voxel. The most common multi-fibre approach here was using a fibre Orientation Distribution Function implemented as part of FSL , presented with relation to each study in Aside from patient-specific dMRI, this review highlighted the use of structural normative connectomes in 13 studies.108 A total of three studies quantified the overlap of VTA with specific neural regions or tracts of interest.81 A similar method used in 10 studies measured the distance (or proximity) of reconstructed contacts/VTA to specific tracts.81 Another method involved assessing quantitative diffusion metrics from tensor-reconstructed tracts, identified in three studies  to other regions in relation to clinical outcomes ’, in which 23 studies were included.82 Importantly, these studies did not measure overlap, proximity, or connectivity to the neurosurgical target (as outlined as part of the inclusion criteria). One study applied graph theory, using the number of streamlines intersecting each region of interest as the network connectivity measure , using MRI-CT fusion overlaid onto, and related to tract reconstruction was a methodological approach .108 A to studies .32,42,49outcomes , left. T measure , right.3A total of 18 studies used morphometric approaches  clusters in the left fusiform and middle frontal gyrus (MFG), bilateral anterior cingulate cortex and reduced volumes in the left insula, left pre-and-post central regions and right putamen volumes were reported in patients with satisfactory motor response to DBS.58 More recently, reduced GMv clusters in the bilateral medial prefrontal cortex (PFC), left angular gyrus, right superior frontal gyrus (SFG) and left MFG were associated with unsatisfactory UPDRS III outcomes.36 Two voxel-based morphometry studies focused on gait-related Parkinson’s disease symptoms. Reduced volumes of bilateral sensorimotor and associative portions of the putamen and increased volumes of left inferior frontal and right inferior temporal regions were associated with increased freezing of gait episodes in 151 patients.37 Reduced volume of the nucleus basalis of Meynert was associated with worsening of gait measures, including variability of swing and stride timing, in 22 patients at a shorter-term follow-up.57 In a subset of 11 patients, swing time variability was associated with reduced nucleus basalis of Meynert volume at a three-year follow-up.With regards to voxel-based morphometry, a positive association of global white matter volume with UPDRS III improvements in a group of 21 patients with idiopathic Parkinson’s disease was reported.48 In contrast, decreases in ventricular volume markers and linear ratios, namely bicaudate ratio, Evans’ index and third ventricular width, were reported in patients with unsatisfactory 6-month UPDRS III outcomes relative to those with satisfactory UPDRS III outcomes.34Non-voxel-based morphometric analyses have been applied in patients with Parkinson’s disease to assess volumetric measures in relation to DBS motor outcomes. In semi-automated approaches, one study identified no association of lateral ventricular volumes in 37 patients with idiopathic Parkinson’s disease on 4-month motor symptom improvement.45 Pre-operative left and right subthalamic nucleus (STN) volumes, used as the implantation target for DBS, were not correlated with UPDRS III outcomes 6-month following implantation in 59 patients with idiopathic Parkinson’s disease.58 Logistic regression outlined right thalamus and bilateral anterior cingulate volumes to be increased in a patient group with satisfactory, relative to a group with unsatisfactory UPDRS III outcomes.58 Additionally, correlations outlined bilateral anterior cingulate volume to be positively associated, whilst left precentral and right postcentral areas were negatively associated with post-operative UPDRS III outcomes.Increases in FreeSurfer-derived volumes of the lateral and third ventricles and reduced volumes of the thalamus were significantly associated with lower UPDRS III outcomes up to a 15-month period in 86 patients with idiopathic Parkinson’s disease.89 In a sample of 31 patients with idiopathic Parkinson’s disease, there was found to be correlations between the reduced cortical thickness of right paracentral and left and right superior frontal clusters with poorer UPDRS III motor outcomes.46 Furthermore, patients with increased cortical thickness in the left and right superior frontal and left precuneus, superior temporal, inferior parietal and superior parietal clusters required lower stimulation voltages for improved outcomes. Other studies reported associations of increased cortical thickness of the left lateral occipital cortex,31 middle and superior frontal,61 and right inferior precentral54‐56 areas with greater UPDRS III motor outcomes. Specific to poorer gait symptom severity, associations were observed for the reduced cortical thickness of left postcentral regions, bilateral premotor and left inferior and superior parietal cortex.Aside from regional volume, cortical thickness is a marker of gross morphology which measures the distance between the pial surface of grey matter and the grey matter-white matter border.A total of 20 studies investigated dMRI data from patients with Parkinson’s disease .35 Other studies seeded from the pedunculopontine nucleus (PPN) in a sample of patients with postural instability,49 the globus pallidus internus (GPi) for assessing camptocormia symptoms,40 and also from patient-specific implantation regions associated with stimulation-induced or non-stimulation-induced dyskinesia (SID) symptoms.53Most studies undertook an OCM approach, with 12 studies exploring contact profiles from seeds at the STN,Due to the large number of studies assessing the relationship between regions associated with contact efficacy across various motor symptoms in Parkinson’s disease, significantly identified structurally connected regions are briefly summarized in 42 Using a classifier to identify efficacious contacts, patients with optimal outcomes showed greater connectivity, with the thalamus, hippocampus, pallidum, primary motor cortex, supplementary motor area (SMA) and SFG. These connectivity features could be used to predict contact efficacy in a validation cohort  with 85% accuracy. In another study, increased axial and radial diffusion metrics extrapolated from streamlined connectivity between the basal ganglia and frontal/motor regions were associated with poorer UPDRS III motor outcomes.32Two studies investigated diffusion tensor metrics in association with UPDRS III motor outcomes. In one study, fractional anisotropy, reflecting the degree of orientation, was used to define the connectivity of streamlines from STN to an atlas parcellation in patients with idiopathic Parkinson’s disease.28 In a cohort of 15 patients, greater eccentricity, theorized to reflect a measure of long-range regional integration, in left frontal and central modules was associated with increased UPDRS III motor outcomes. Receiver operating curves identified left medial and dorsolateral superior frontal gyri and inferior frontal gyri in the left frontal module and central areas including the left SMA and cingulate gyri to be greatest associated with motor outcomes.Network characteristics derived from graph theory were applied to whole-brain, atlas-based tractography in one study.28 the dentatorubrothalamic tract (DRTT)60 and left STN to the ipsilateral nigrostriatal pathway  was associated with greater clinical motor outcomes in relation to the hyperdirect pathway , left,28 pathway , right.625 Rigidity improvements were associated with overlap of pallidofugal pathways  gyrus, pre-SMA and cerebellar vermis in patients with generalized and cervical dystonia were reported in a group of patients with optimal BFMDRS and TWSTRS improvements, respectively, relative to sub-optimal responders.63 A correlational analysis identified a significant association of increased grey matter density in the left MC gyrus and ventral SMA clusters with the clinical pre-and-post-operative motor score change  was significantly correlated with BFMDRS improvement in 10 patients with focal and segmental dystonia .6968 Whilst both implantation areas offered sufficient motor symptom reduction, ventral profiles achieved greater efficacy and were associated with greater connectivity to the left and right primary sensory cortex. Dorsal profiles were associated with a stronger connectivity to the left and right premotor cortex (PMC) and pre-SMA. In 39 patients with generalized dystonia, stronger connectivity to the left dorsal primary motor cortex, lateral frontal, inferior parietal, and lateral temporo-occipital regions were associated with positive UDRS outcomes.66 Negative UDRS outcomes were associated strongest with connectivity to the left medial PFC. In 19 patients with cervical dystonia, greater connectivity to the putamen was associated with positive motor outcomes.67 Parcellation of the putamina outlined greater pallidal connectivity to a middle (primary motor cortex) area to be significantly correlated with greater motor outcomes.Three studies applied OCM . Dorsal Identified tremor studies focused solely on the use of tractography-based analyses . In a sample of 12 patients with either tremor-dominant Parkinson’s disease or essential tremor, connectivity to the precentral gyrus (PCG), supplementary and cingulate motor area (CMA), lateral premotor cortex (LPMC) and superior cerebellar peduncle (SCP) were associated with greater FTM improvements.78 This result was obtained by training on a cohort of 83 patients and validated on 14 patients. In a cohort 20 patients with essential tremor and 20 patients with dystonic tremor, the role of decussating and non-decussating DRTTs were explored.82 Leave-one-out cross-validations using group tract maps weighted by contralateral tremor improvement identified the pattern of the DRTT (combined non-decussating and decussating fibres) as predictive of outcomes for patients with essential tremor, and the pallidothalamic tract as predictive of outcomes for patients with dystonic tremor.Two studies seeded connectivity from contacts at the VIM/ventral oral posterior border of the thalamus and tested the predictive ability of normative connectomes using cross-validation. Structural connectivity to primary, supplementary and premotor cortices, sensory cortex and a tract corresponding to the DRTT were outlined as significant predictors for contralateral essential tremor improvements.In this review, 60 studies identified structural features from MRI that could possibly account for and predict motor outcomes from DBS in patients with Parkinson’s disease, dystonia syndromes and tremor. Given the large number of studies identified in this review, structural features appear to be a promising approach. Studies highlighted a variety of morphometric and connectivity-based measures across all movement disorders, along with iron-based features applied specifically to patients with Parkinson’s disease. Importantly, the diversity of reported markers and techniques highlights the lack of unified understanding of aetiologies and exemplifies the clinical heterogeneity of pathophysiological mechanisms across disorders.111‐113 research has identified complex interfacing across whole-brain networks to give rise to motor control.115 Alterations to regions or connections within systems have been shown to result in disease or disorder.116 Consequently, our understanding of DBS effects extending the local site of stimulation corroborates a systems-level approach to network neuromodulation, by therapeutically disrupting the underlying pathological circuitry of a given movement disorder.117‐120 Indeed, the change in view of diagnostic constructs is nicely summarized by the suggestion of a nomenclature change of DBS to ‘electrical neuro-network modulation’ which better reflects DBS mechanistically and how movement disorders (and perhaps most disorders and diseases) should be treated.121Viewing motor disorders as aberrations to widespread networks is now recognized as being paramount to enhance our understanding of disorder aetiology and maximize therapeutic benefits received from DBS. Although the basal ganglia have been central to our understanding,123 it would make sense that the structural architecture of the brain—in terms of grey and white matter integrity—would instantiate a mediating factor for therapeutic efficacy. Interesting work has indicated that both structural grey matter volumetric changes and white matter changes can occur following neuromodulation from DBS.124‐127 However, it remains unclear whether these findings are a result of the intervention itself, or pathological processes related to circuitry change within the disorder.The interaction between neuromodulation and brain structure is unclear. Given that neuromodulatory effects have been shown to be sensitive to changes in brain state,128 The theoretical models of basal ganglia functioning have formed the basis for our understanding of motor control.130 Classically defined ‘direct’, ‘indirect’ and ‘hyperdirect’ basal ganglia pathways have been popularly applied as physiological mechanisms for control of the basal ganglia-thalamo-cortical loop, with prominence for Parkinson’s disease,131 aiding our understanding of circuitry dysfunction at a systems level.132Relative to other movement disorders, the neuropathology of Parkinson’s disease is well-established.133 showing susceptibility to enhanced localized iron deposition134 and dopaminergic neuronal loss post-mortem.135 The positive associations of increased iron-related presence for Parkinson’s disease in the STN and SN indicate a role of dopaminergic pathology in the mediation of DBS efficacy.44 Interestingly, STN GMv was not associated with DBS outcomes but was reduced relative to healthy controls,45 a finding that has also been observed at 7 Tesla.136 Volumetric decreases of the putamen,37 thalamus59 and ventricular enlargements,34 may perhaps better reflect progressive disease changes which associate more closely with DBS efficacy. In contrast, STN volumes may reflect a more general marker of the disease’s presence. Animal models suggest that dopaminergic midbrain neuronal loss results in marked reductions of STN efferent connections in the hyperdirect pathway, and synaptic changes with the pallidum.138 However, given that Parkinson’s disease is a neurodegenerative disorder and dopaminergic neuronal loss continues through the late stages of progression,139 it remains unclear as to why volumetry of the STN may not be concordant with changes in motor symptoms in the disease.Neurodegeneration of the substantia nigra (SN) pars compacta is a main hallmark of Parkinson’s disease presence and progression,60 As mentioned, tract importance underpins the necessity to focus on extending outside the local stimulation area. Corroborative findings for structural variability and connectivity from contacts deemed as efficacious in cerebellar and widespread cortical regions, particularly frontal and sensorimotor, highlight the whole-brain network aspect for determining DBS response.58White matter tract importance for DBS outcomes in Parkinson’s disease was evident in the present review. Closer contact proximity and increased overlap of pallido- and nigrofugal basal ganglia pathways appeared to be beneficial for improving clinical motor outcomes following DBS.141 Importantly, regions constituting non-dopaminergic systems were pathologically highlighted in the current review. In particular, the PPN and nucleus basalis of Meynert constitute centres for large cholinergic afference and are regions that have emerged as susceptible in patients with Parkinson’s disease.142‐144 Importantly, cholinergic neurons are also present in the striatum and have been shown to regulate medium spiny neurons of direct and indirect basal ganglia pathways,145 and regulate dopaminergic release in the striatum.146 The cholinergic system has been identified to play a key role in mobility functioning with alterations resulting in postural instability, gait issues and falling in patients with Parkinson’s disease.148 Here, we observed supporting evidence of PPN and nucleus basalis of Meynert structural variability as potential structural correlates for axial symptom response in patients with bradykinesia and predominant posture and gait issues.57 Whilst the mechanisms for how cholinergic systems are disrupted in patients with Parkinson’s disease requires further investigation, this review sheds light on the importance of recognizing the system-level cascade of disorder pathology and potential DBS targets for patients with axial-dominant symptoms.Dysfunctional neurotransmission of dopamine has dominated as the primary pathophysiological explanation for Parkinson’s disease symptoms, given its fundamental modulatory role within the cortico–basal–ganglia architecture.149‐151 This is evident from the current review with studies identifying patients with focal , segmental and generalized dystonia’s along with clinical phenotypes such as X-linked dystonia-parkinsonism.Dystonia syndromes are highly prevalent movement disorders, but aetiologies are poorly understood and heterogeneous.149 However, the GPi of the basal ganglia are the most favourable nuclei for optimal therapeutic benefits, indicating analogous similarity in circuitry dysfunction.152 Electrophysiological GPi recordings support abnormal pallidal signalling within the thalamo-cortical system.154Amelioration of atypical functioning may be achieved by GPi-DBS resulting in therapeutic dystonic relief. Compared with the observation that STN volumes were not associated with DBS outcomes for Parkinson’s disease,45 GPi volumes were associated with importance for motor outcomes in primary dystonia.71 The reasons for this distinction may be due to several factors. First, the manual delineation technique used for GPi reconstruction may offer a more accurate estimation of volumetry. Automatic approaches may be less sensitive to quantifying small subcortical nuclei, especially given that T1-weighted MRI were used, which provides poor contrast for boundary estimations of the STN. Second, the therapeutic benefits obtained from patients with dystonia syndromes are not instantaneous in comparison to Parkinson’s disease, indicating more gradual neuroplastic changes underpin neuromodulatory effects.155 Pallidal volumes may, therefore, play a more prominent role in promoting longer-term plastic changes, especially given that they comprise the primary output nodes of the basal ganglia.Unlike Parkinson’s disease, primary dystonia syndromes have no evidence of neurodegeneration and no hallmark brain-based pathologies present.65 The dorsal striatum is a key module for basal ganglia input and plays a major role in action selection.156 The dorsal striatum appears to be particularly susceptible in genetic dystonic syndromes with large volumetric reductions evident in late-stage X-linked dystonia-parkinsonism.157 Despite initial evidence indicating the caudate to primarily be involved in cognition and the putamen in motor functions, extensive and widespread prefrontal and sensorimotor cortico-striatal connectivity and unclear anatomical boundaries indicate functional integration of regions.158 Further evidence suggests that the caudate nucleus is susceptible to genomic-based changes in Huntington’s disease,159 and microstructural changes in cervical dystonia.160 Striatal dysfunction is regarded as a key mediator of abnormal cortical plasticity that is associated with dystonia syndromes.162 Modulation of this abnormal plasticity has been proposed to underpin the therapeutic effects of DBS, highlighting the area as key to mediating clinical outcomes.163Other identified basal ganglia nuclei included the caudate and putamen, making up the dorsal striatum, from which reduced volumes and signal abnormalities were indicative of poorer DBS response.164 and synchronization and overactivation of sensorimotor networks are well-defined features of dystonia syndromes.165 Negative correlations between the somatosensory cortex and cerebellum, derived from functional MRI, have been associated with favourable outcomes in dystonia and present as a signature of circuitry dysfunction.167 In this review, pallidum to putamen-primary motor cortex connectivity as a predictor for outcomes in patients with isolated cervical dystonia is in line with the abnormal motor component of dystonia.168 DBS has been indicated to normalize oscillatory coherence with and decrease the overactivity of the primary motor cortex.170 Furthermore, identified optimal outcomes arising from ventral GPi implantations with association to increased connectivity with primary somatosensory cortex provide additional support for sensorimotor networks as a prominent marker for neuromodulatory efficacy.68The association of basal ganglia regions with cerebellar and sensorimotor cortical activity is the primary theory underpinning dystonia pathophysiology. Abnormalities of sensory processing,41 Further exploration of these circuits may help to elucidate a therapeutic target aimed at altering sensorimotor networks to control dystonic and postural symptoms.Finally, although indicated as a symptom of Parkinson’s disease, efficacious contacts determined by GPi-primary somatosensory cortex and STN-pre/supplementary motor cortex connectivity in patients with camptocormia highlights the salience of sensorimotor network involvement for abnormal posturing symptoms across disorders.171 Dystonic tremor is typically diagnosed with postural abnormalities and irregular tremor amplitude and frequency.172 Parkinsonian tremor typically affects the upper extremities and can occur as either action tremor or rest tremor (4–6 Hz).173Despite essential tremor being the most prevalent movement disorder worldwide, the aetiology (including other tremor subtypes) is not well understood. Essential tremor manifests as a kinetic tremor (4–12 Hz) that can affect all parts of the body.174 However, this theory has fallen out of favour with a lack of evidence for both activation using positron emission tomography,175 and post-mortem structural change in patients with essential tremor.176 Instead, evidence supports essential tremor as a neurodegenerative disorder of the cerebellum due to observations of cellular neurodegeneration in post-mortem examinations.177In this review, cerebellar involvement in clinical outcome mediation was identified across multiple structural MRI domains and tremor disorders. Initial pathomechanisms for essential tremor implied the inferior olivary nucleus as a centre for tremerogenesis.179 Dysfunction of cortico-cerebellar circuitry has been proposed to result in excessive oscillatory feedback and the consequent tremor generation.181 The neuromodulation of a ‘tremor network’ through cerebellar circuitry has been proposed to disrupt aberrant oscillatory activity, inducing corrective functioning and alleviating tremor activity.76 Two cerebellar tracts that have been heavily implicated in tremor pathophysiology are ‘short’ and ‘long’ loops. The former is said to reflect a short-range circuit comprising the dentate nucleus (DN) of the cerebellum and the inferior olivary nucleus, constituting a dentato-olivio-cerebellar pathway. The long loop pertains to projections from the DN towards the thalamus for cortico-cerebellar connectivity, likened to the anatomical course of the DRTT.180The cerebellum plays a crucial role in calculating and predicting movements based on error in the form of large-scale sensorimotor feedback.79 but also in whole-brain exploratory approaches.82 Whilst the study identifying no association of contact proximity to the DRTT may have been restricted by a small sample size,81 deterministic tractography used in the study has outlined a poorer ability to reconstruct the DRTT, relative to probabilistic tracking.183 Importantly, tractography performance is dependent upon the tract(s) of interest, and the purpose for reconstruction such that probabilistic tractography does not always offer superior efficacy for tract reconstruction.185In the present review, dMRI outlined compelling evidence for DRTT involvement in tremor suppression across multiple tremor pathologies. Importantly, this was the case not only when the DRTT was explicitly investigated,80 Importantly, the role of motor regions indicated in Parkinson’s disease showed contrasting results across studies. Motor region connectivity proved beneficial in tremor-dominant Parkinson’s disease and tremor subscales of the UPDRS III,80 but also associated with poor contact efficacy on the UPDRS III tremor component in another study.50 The divergence in results here raises an important point regarding clinical heterogeneity, disorder understanding and therapeutic targeting that is discussed in the following section.Evidence for sensorimotor feedback being involved in tremor mechanisms was also indicated across studies. Connectivity with the cerebellum, brainstem and sensorimotor cortices was indicative of greater essential tremor improvement.187 Understanding the contribution of each brain region presents an incredibly complex task and requires patient cohorts that are as homogenous as possible to derive clinically meaningful inferences.Movement disorders are rarely monosymptomatic and will often present with myriad symptoms, reflective of widespread clinical heterogeneity.188 Identifying and targeting symptom-specific networks are the next steps for individualizing DBS treatment to optimize therapeutic benefits at an individual level.189As mentioned, we observed many regions associated with positive outcomes to be associated with negative outcomes in other studies. Furthermore, networks pertaining to a specific symptom of a disorder likely constitute different white matter pathways and brain regions. For example, rigidity and bradykinesia likely constitute different circuitry pathologies which may not be optimally therapeutically targeted under conventional STN DBS. A lack of focality on specific network targeting is exemplified by findings that DBS targeting of STN and GPi appear to modulate extremely similar networks in patients with Parkinson’s disease.80 In such cases, derived markers cannot be strictly predictive as they reflect a potential disease/disorder correlate within the sample to which the model was fit.An important implication present in this review is the utility of markers that are inferred through means of association and correlation, versus prediction. Although many articles explicitly outlined the ‘predictive’ ability of identified structural marker(s), analyses were restricted to correlations/associations.190 Leave-one-out cross-validation reflects a prediction of a single case (i.e. patient) by training a statistical model on the rest of the data and repeating this iteratively until all cases have been modelled.191 Studies utilizing this approach enable greater finding generalisability than associations constructed from the entire data set only, 82 by increasing chances of avoiding overfitting. However, even in leave-one-out cross-validation, the model is still only internally validated in the group.192 Studies applying external validation, through training and testing statistical models on independent data sets, offer perhaps the greatest representation of prediction. This was observed for single-centre splitting,61 and cross-centre testing and training sets.193 Cross-centre validation remains one of the best ways to construct generalizable, prognostic models.Validation of these markers through the means of testing on unseen (independent) data reflects a more robust method to infer finding generalisability.Determining what is meant by ‘response’ to DBS is a subjective matter, complicated by symptomatic differences, surgical factors, disorder severity, clinical follow-up and patient expectations. Additionally, smaller improvements (or declines) in symptoms that are subjectively more severe may not translate effectively when quantifying pre-and-post score changes, raising concern over the sensitivity towards patient-centred improvement.In the present review, we identified a range of grouping thresholds and follow-up points used to distinguish patients with higher versus lower motor improvements. Determining which grouping threshold to use to dichotomize patients, and how to calculate the change are incredibly important aspects that will impact the inferences and conclusions derived from a study. Arriving at standardized notions for response level for treatment outcomes is an area that requires work but will massively benefit the quality of research.195The number of studies identified in this review using dMRI outlines the interest in assessing aspects of white matter connectivity as biomarkers for clinical outcomes from DBS. In theory, patient-specific dMRI enables greater insight and inference for studies assessing DBS response given that it is reflective of the patient(s) in question. Furthermore, patient-specific dMRI is showing increasing clinical utility for optimizing intra-operative planning and targeting of DBS electrodes in relation to white matter fibres.196‐198As identified in the review, sample sizes of studies utilizing patient-specific dMRI tended to be small in comparison to studies utilizing normative connectomes. Whilst not patient-specific, normative connectomes do enable larger sample sizes of patients to be analysed in cases where dMRI data is not routinely acquired  making it a time and cost-effective technique. In addition, pitfalls of poor test-retest reliability of individual dMRI data may be overcome by the greater signal-to-noise ratios offered by the larger sample sizes, and the specialized acquisition protocols that have been implemented during acquisition.199The question of to what extent statistical inferences may be improved by the use of disease-matched normative connectomes is undetermined as similar predictive abilities with healthy normative connectomes for post-operative outcomes have been observed.200 Additionally, resolution of connection direction cannot be achieved, making efferent and afferent connectivity indistinguishable.201 Furthermore, the exact relationships between diffusion-derived metrics and white matter microstructure remain elusive.203Whilst both applications will continue to improve our understanding of developing predictive biomarkers for DBS outcomes, the fundamental limitations of dMRI still hold for both. Inaccuracies of tract reconstruction in areas of crossing-fibres make the delineation of specific tracts an issue.Techniques focused on structural MRI assessment for post-operative motor outcome prediction offer great promise to identify patients more likely to benefit from DBS. In this review, we identified many applications to patient cohorts with Parkinson’s disease, dystonia syndromes and tremor. The integral role of cortical, subcortical, and cerebellar networks on the mediation of DBS response are observed across MRI methods and movement disorders. The variety of techniques identified in this review demonstrates the possibilities on the horizon for structural features from MRI. Differences of cortical thickness and brain volumes present corroborative markers that may be useful to inform candidate selection. Advancements of dMRI approaches to probe white matter tracts are helping to extend our understanding of disorder pathology and to provide alternative therapeutic targets. Future applications pose great promise to aid prediction of outcomes at the individualized level, and to help elucidate mechanisms that underly disorders.fcad171_Supplementary_DataClick here for additional data file.


Sarcoidosis is a multi-organ systemic disease that presents with several clinical manifestations, and patients can develop neurologic complications. Neurosarcoidosis may be life-threatening; therefore, early recognition and treatment are key. Here, we present a case of a 55-year-old African American male who presented with a complaint of dizziness and left-sided weakness; he ultimately received a diagnosis of neurosarcoidosis after elaborate radiographic investigations and bladder mass biopsy. Neurosarcoidosis remains a diagnostic dilemma as it can clinically and radiographically mimic multiple conditions including multiple sclerosis, central nervous system lymphoma, multiple myeloma, and progressive multifocal leukoencephalopathy. Neurosarcoidosis is a challenging medical condition where up to 70% of patients present with neurological manifestations rather than already having a known systemic diagnosis . It is dThis case was previously presented as a poster at the Florida Society of Rheumatology Annual Fellow Poster Presentation on July 09, 2022.A 55-year-old African American male, with a medical history of substance use, cerebrovascular accident, hepatitis B, recently diagnosed with right lower extremity deep venous thrombosis on anticoagulation presented to the hospital with complaints of dizziness, blurry vision and left-sided weakness of one-day duration. Of note, the patient had had multiple emergency department visits within the past month for similar left-sided leg pain and falls. He had been treated for cellulitis and pain. This time computed tomography (CT) of the brain was ordered and revealed large areas of white matter hypodensities in bifrontal lobes as well as small areas of cortical hypodensities in the right anterioinferior frontal lobe Figure .This was initially concerning for acute infarct versus subacute post-traumatic changes. Other possible differentials were reversible posterior leukoencephalopathy or neoplastic process given the local mass effect. Neurological examination was non-focal and cranial nerves II-XII were intact. A painful range of motion was noted in the lower extremity; however, muscle strength was noted to be 5/5. Additional findings on the physical examination included bilateral lower extremity edema left more than right, oral thrush and right axillary lymphadenopathy. The stroke protocol was initiated, and the patient was admitted to the hospital. Neurology and Hematology Oncology services were consulted for further evaluation.Magnetic resonance imaging (MRI) of the brain with contrast revealed extensive enhancing dural nodularity along bilateral frontal convexities and anterior falx associated with extensive nodular leptomeningeal enhancement along the bilateral frontal lobes, suprasellar cistern, right sylvian fissure, and right basal ganglia with associated extensive bilateral frontal vasogenic edema and mass effect on lateral ventricles Figures , 3.The differentials were narrowed down to central nervous system (CNS) lymphoma versus neurosarcoidosis. Due to concerns of CNS lymphoma, steroids were initially withheld pending cerebrospinal fluid (CSF) analysis. CT of the chest without contrast was done and revealed sub-centimeter mediastinal, bilateral hilar, and right axillary lymphadenopathy Figure . A core CT of the abdomen and pelvis with contrast was ordered for further assessment of lymphadenopathy that discovered a 2.6-cm bladder wall tumor concerning for neoplasm. There was also bilateral iliac chain and retroperitoneal adenopathy suspicious for metastatic disease. The patient underwent transurethral resection of the bladder tumor. The pathology revealed noncaseating granulomas Figures , 6.On hospital day 7, the patient developed new-onset left-sided weakness including reduced grip strength and left-sided facial droop. Brain imaging revealed persistent vasogenic edema. After a discussion with all the specialists, the decision was made to initiate steroids prior to CSF analysis. Acid-fast bacilli (AFB) stains from the axillary lymph node as well as the bladder tumor returned negative. At this time, a lumbar puncture was performed that was negative for infection or malignancy. The CSF angiotensin-converting enzyme (ACE) levels were within normal limits Tables , 2.The patient clinically improved after the initiation of steroids and a repeat MRI scan of the brain showed moderate interval improvement with persistent leptomeningeal enhancement and resolution of the previously present mass effect on frontal horns. The diagnosis of neurosarcoidosis was favored given bilateral hilar adenopathy on the chest CT scan, improvement in imaging findings following steroid administration, and noncaseating granulomas found in the bladder lesion. Neurosurgery and Oncology did not favor brain biopsy at this time. The patient was discharged on dexamethasone with instructions to follow up with Rheumatology as an outpatient.Up to 70% of patients with neurosarcoidosis present to medical care with their neurological manifestations rather than already having a known systemic diagnosis . As the Neurosarcoidosis exhibits variable degrees of infiltration in the brain resulting in focal or disseminated nodules or plaques affecting particularly the basal meninges. The granulomatous infiltration may extend into the cortex or white matter causing parenchymal lesions -8. This In 2018, the Neurosarcoidosis Consortium Consensus Group developed a diagnostic approach for neurosarcoidosis, adapted from 1999, that described possible, probable and definite neurosarcoidosis . AlternaThere are several conditions that neurosarcoidosis can mimic. One of them is multiple sclerosis (MS), given the radiologic findings on MRI besides relapsing-remitting course of the disease as well as dissemination of the MRI lesions in space and time. Cognitive and neuropsychiatric presentation in the context of parenchymal brain lesions argues against MS, and certainly, coexisting peripheral nervous system involvement or myopathies are distinctive features of neurosarcoidosis . AdditioThis case is not only a diagnostic challenge but also a therapeutic one due to social constraints. Patient's comorbidities, in addition to homelessness, made it challenging to ensure follow-up with various specialists. Several works of literature have shown sarcoidosis to be a disease that affects those with health disparities -15. AccoNeurosarcoidosis poses a diagnostic challenge as it can imitate other neurological diseases, including CNS lymphoma and multiple sclerosis. In addition, the prognosis of neurosarcoidosis varies, with some recovering completely, while others have a chronically progressing, waxing, and waning course. Moreover, it imposes a significant economic burden on the payer, especially in the first year following diagnosis as patients require several specialist visits to manage sarcoidosis-related comorbidities, making it a therapeutic challenge.


Aspergillus infection. He presented with persistent fever with left-sided weakness of the upper and lower limb for the past 15 days accompanied by profound visual loss in the left eye. A neurological examination revealed a left-sided ataxic hemiparesis with a significant reduction of power in both upper and lower limbs with dysarthria. He underwent neuroimaging which revealed a fresh non-hemorrhagic infarct in the left thalamocapsular and left parieto-occipital regions, suggestive of a stroke. A positron emission tomography/computed tomography scan revealed a diffuse low-grade uptake  associated with a circumferential wall thickening involving the ascending aorta, arch of the aorta, and descending and abdominal aorta, suggestive of active large-vessel vasculitis. On examination, his visual acuity was 6/9 unaided in the right eye and perception of light with inaccurate projection in the left. A dilated fundus examination revealed multiple hemorrhages, cotton-wool spots, and areas of retinal thickening associated with a hard exudate in the right eye. A similar picture was seen in the left eye with the additional findings of a large (1 DD x 1 DD) subretinal whitish-yellowish mass with surrounding superficial retinal hemorrhages in the superior quadrant. A B-scan through the subretinal revealed non-visualization of the retinal pigment epithelium-Bruchs membrane layer with a large subretinal mass with a basal hyporeflective area and hyperreflective areas superiorly, suggesting a choroidal Aspergillus infection with infiltration of the overlying retina but without vitreous seeding. He was treated with anti-epileptics, oral and injectable blood thinners, oral antihypertensives, and oral antidiabetic medication. Intravenous methylprednisolone 1 g once daily was administered for five days, followed by oral prednisolone in tapering doses. In view of the ocular findings and the presumed diagnosis of ocular aspergillus, oral voriconazole 400 mg daily was added. At the last follow-up, the subretinal mass had completely resolved with a residual area of pigmentary degeneration with loss of retinal layer differentiation on the B-scan. There was also a marked reduction in the hemorrhages and cotton-wool spots in either eye, suggesting a marked improvement of the retinal vasculitis. A larger dataset would be needed to confirm a potential causative role for systemic fungal infections in large-vessel vasculitis.We report the systemic, ocular, and investigational findings of a 51-year-old male patient with large-vessel vasculitis and presumed ocular  Candida spp, Aspergillus spp., and Mucormycosis spp. Aspergillus is a highly prevalent saprophyte fungus, with infections commonly involving the lungs and sinuses [Ocular fungal infections are a commonly encountered cause of visual morbidity and may potentially involve external structures such as the cornea, eyelids, or the internal tissues of the eye including the retina and choroid. Common fungi include  sinuses .Aspergillus intraocular infection produces panuveitis or endophthalmitis with highly significant ocular morbidity. Endophthalmitis, when it occurs after trauma, intraocular surgery, or following corneal infections, is termed exogenous and is usually encountered after cataract surgery. Endophthalmitis without an antecedent intraocular surgery or trauma is termed endogenous and is largely associated with an immunocompromised state such as that induced by human immunodeficiency virus (HIV) infection or following long-term immunosuppressive treatment and is due to hematogenous dissemination [mination .We report the systemic, ocular, and investigational findings of a 51-year-old male patient with magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) findings suggestive of large-vessel vasculitis and an ocular examination suggestive of extensive retinal vasculitis and simultaneous intraocular aspergillus infection.A 51-year-old male patient presented with persistent fever and left-sided weakness involving both the upper and lower limb for the past 15 days accompanied by slurring of speech and profound visual loss in the left eye. He was a known case of diabetes mellitus (type 2) and systemic hypertension. There was no history/symptoms suggestive of COVID-19 infection and he had been vaccinated (two doses).Significant past history included episodes of vertigo with difficulties in walking and sitting for 15 days. He had recently been treated (14 days earlier) for a cerebrovascular accident and had been discharged on a combination of oral clopidogrel 150 mg with aspirin 75 mg once a day, a combination of oral telmisartan 40 mg with metoprolol succinate 25 mg twice a day, oral prazosin 5 mg once a day, oral atorvastatin 40 mg once daily, oral cilnidipine 20 mg twice daily, and oral glimepiride 1 mg twice a day.On systemic examination, he was conscious and oriented with normal vital parameters . Examination of the cardiovascular and respiratory systems was within normal limits. A neurological examination revealed a left-sided ataxic hemiparesis with a significant reduction of power in both upper and lower limbs with dysarthria.Based on a clinical diagnosis of stroke, he underwent neuroimaging (MRI brain with gadolinium with MR angiography of the brain) which revealed a fresh non-hemorrhagic infarct in the left thalamocapsular and left parieto-occipital regions Figures , 1B. ChrA PET/CT scan was administered to the patient with the use of 370 MBq of 18 fluorodeoxyglucose (FDG). Concomitantly, non-ionic intravenous contrast was administered. Areas of abnormal FDG uptake included scattered areas of reduced uptake in the entire brain more prominently in the parietal, medial temporal basal ganglia, and cerebellar regions. A diffuse low-grade uptake  was associated with a circumferential wall thickening involving the ascending aorta, arch of the aorta, and descending and abdominal aorta Figure . SimilarThe significant laboratory investigations are summarized below in Table The investigations suggested a pro-inflammatory state, as noted by the elevated leucocyte count, C-reactive proteins, and erythrocyte sedimentation rate. A baseline search for autoimmune antibodies was negative but the MRI and PET/CT investigational findings suggested extensive systemic vasculitis. The patient had mildly deranged renal and hepatic functions as well. A joint rheumatology/neurology consult evaluated these findings and agreed on a diagnosis of active large-vessel vasculitis with the need for early intravenous pulse steroid therapy.Aspergillus infection with infiltration of the overlying retina but without vitreous seeding. , oral aspirin 75 mg once a day, oral atorvastatin 20 mg once a day, oral antihypertensives , injectable enoxaparin 40 mg twice a day, injectable piracetam 1 g twice daily, oral modafinil 100 mg once daily, and oral glimepiride 1 mg twice a day. Intravenous methylprednisolone 1 g once daily was administered for five days, followed by oral prednisolone (50 mg/day) once a day in tapering doses (10 mg weekly). In view of the ocular findings and the presumed diagnosis of ocular At the first follow-up (six weeks), there was a significant reduction of the subretinal mass which was corroborated by a reduction in the mass size on the B-scan. At the last follow-up, the subretinal mass had completely resolved with a residual area of pigmentary degeneration Figure  with losWe report the clinical and investigational findings of a middle-aged male with MRI and PET/CT-proven large-vessel vasculitis associated with a presumed ocular aspergillus infection and its successful treatment with a combination of oral steroids and voriconazole.Candida spp, Aspergillus spp., and Mucormycosis spp. Aspergillus is an innocuous, highly prevalent saprophyte fungus, and its infections commonly involve the lungs and sinuses. Commonly encountered species include Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, and Aspergillus terreus.Ocular fungal infections are an important cause of ocular morbidity and may involve various tissues including the external structures such as the cornea, eyelids, lacrimal apparatus, or internal tissues including the retina and choroid. Common causative organisms include Aspergillus spp. may involve the external tissues of the eye, commonly the cornea, but may also cause conjunctivitis and lacrimal system infections. The ingress of Aspergillus infection into the eye produces panuveitis or endophthalmitis with highly significant ocular morbidity. Exogenous endophthalmitis usually occurs after trauma, intraocular surgery, or following corneal infections. Endophthalmitis without an antecedent intraocular surgery or trauma is termed endogenous and is largely associated with an immunocompromised state such as that induced by HIV infection, malignancy, following long-term immunosuppressive treatment, and is due to hematogenous dissemination from a systemic focus of infection [nfection ,2.Aspergillus-induced endophthalmitis. Logan et al. reported the clinical findings and management of a 78-year-old lady with uniocular visual loss. She was on a short course of steroids for possible giant-cell arteritis and developed panuveitis over a period of five days. A vitreous biopsy and subsequent culture on Sabourauds agar revealed Aspergillus fumigatus and she was initiated on oral voriconazole 400 mg twice a day for 24 hours, followed by a maintenance treatment at a dose of 200 mg twice a day for a two-week course for complete resolution [Aspergillus fumigatus endophthalmitis following an aortic root replacement eight months earlier [Aspergillus iris granuloma. Some of these patients, however, reported intravenous infusions a few days before the onset of symptoms or pre-existing pulmonary disease with presumed Aspergillus infection [Rarely, immunocompetent individuals with no previous risk factors may also be affected by solution . Rana etnfection -17.Mycobacterium tuberculosis, giant cell arteritis with Burkholderia, and polyarteritis nodosa with hepatitis B virus, hepatitis C virus, and HIV infections. Similarly, the role of Aspergillus spp. as a causative agent of cerebral vasculitis and infarction is increasingly being recognized. Roberts et al. reported the case of a 71-year-old female who was treated for a history of malaise and headaches. Post-mortem findings included a thrombosis of the basilar artery, with extensive infiltration of the wall with the characteristic branching septate hyphae [There is a complex interaction between systemic infections and vasculitis. A large body of research has linked Takayasu arteritis with e hyphae . Haddad e hyphae .Possible mechanisms of interplay between infection and immunity include direct mechanisms such as hematogenous septic emboli or direct invasion of the blood vessel walls. Indirect mechanisms include (A) activation of T and B cells: infections may stimulate an autoimmune response due to shared epitopes between pathogens and host or upregulated heat shock proteins. Circulating toxins may act as superantigens and these could induce oligoclonal activation of T cells. (B) Immune complex-mediated damage: this represents a type III hypersensitivity where the infectious organisms act as antigens. These immune complexes are lodged within vessel walls and stimulate an immune response. (C) cell-mediated hypersensitivity type IV: exposure to antigens may attract lymphocytes which release cytokines that cause further inflammatory cell activation and tissue damage .Aspergillus infection. The diagnosis was based on a positive serum galactomannan test, and the therapeutic response to voriconazole negated the need for a diagnostic vitrectomy with the attendant risks but we agree a diagnostic vitrectomy would have been confirmatory and allowed species identification as well. The fundus/OCT picture at diagnosis was non-specific for diagnosing retinal vasculitis and there is a possibility of concurrent diabetic retinopathy which also presents with cotton-wool spots/hemorrhages. The OCT showed extensive capillary non-perfusion which is a feature of both disease conditions. However, the marked improvement in the clinical picture with the resolution of the cotton-wool spots/hemorrhages suggests a significant vasculitic component that responded to steroid therapy. We opted not to perform a vitrectomy as we felt the clear vitreous without seeding would not permit any significant microbiological result. For similar reasons, we opted to treat this patient conservatively, with oral voriconazole and regular monitoring. The duration of therapy was determined by an infectious disease consult.The patient we report had large-vessel vasculitis with presumed ocular Aspergillus (presumably hematogenous) but it is not possible to confirm a causative role of the fungal infection for the large-vessel vasculitis, and the dual pathologies may simply represent an associated secondary infection due to diabetes mellitus or other undefined factors. A larger dataset would be needed to confirm a potential causative role of systemic fungal infections in large-vessel vasculitis.This patient had a combination of large-vessel vasculitis with ocular The patient we report presented with an autoimmune pathology in the form of large-vessel vasculitis which had its clinical correlates in the stroke/dysarthria with imaging correlations on the MRI and PET/CT scans. There was extensive retinal vasculitis possibly due similar pathogenic mechanism. This had its clinical correlates in the hemorrhages and cotton-wool spots which showed a significant improvement following steroid therapy. Similarly, there was marked systemic improvement.Aspergillus which correlated well with the B-scan and serological studies. The use of oral voriconazole led to a complete resolution with residual retinal atrophy. We highlight this dual pathology which may be a result of an unrelated secondary invasive fungal infection in a patient with diabetes mellitus or may suggest a causal role of the infection in the development of vasculitis. A larger dataset would be needed to study this possibility.Additionally, there was an associated intraocular infection presumably


A bidirectional functional link between vestibular and fear-related disorders has been previously suggested.To test a potential overlap of vestibular and fear systems with regard to their brain imaging representation maps.By use of voxel-based mapping permutation of subject images, we conducted a meta-analysis of earlier functional magnetic resonance imaging (fMRI) studies applying vestibular stimulation and fear conditioning in healthy volunteers.Common clusters of concordance of vestibular stimulation and fear conditioning were found in the bilateral anterior insula cortex, ventrolateral prefrontal cortex and the right temporal pole, bilaterally in the adjacent ventrolateral prefrontal cortex, cingulate gyrus, secondary somatosensory cortex, superior temporal and intraparietal lobe, supplementary motor area and premotor cortex, as well as subcortical areas, such as the bilateral thalamus, mesencephalic brainstem including the collicular complex, pons, cerebellar vermis and bilateral cerebellar hemispheres. Peak areas of high concordance for activations during vestibular stimulation but deactivations during fear conditioning were centered on the posterior insula and S2.The structural overlap of both networks allows the following functional interpretations: first, the amygdala, superior colliculi, and antero-medial thalamus might represent a release of preprogramed sensorimotor patterns of approach or avoidance. Second, the activation (vestibular system) and deactivation (fear system) of the bilateral posterior insula is compatible with the view that downregulation of the fear network by acute vestibular disorders or unfamiliar vestibular stimulation makes unpleasant perceived body accelerations less distressing. This also fits the clinical observation that patients with bilateral vestibular loss suffer from less vertigo-related anxiety.The online version contains supplementary material available at 10.1007/s00415-023-11568-7. There is increasing evidence, based on animal models and studies in humans, that the vestibular system is connected via multiple pathways with the functional structures relevant for fears and anxiety and cognitive and emotional effects –5. TheseClinically, this is evident in patients with vestibular disorders showing a high comorbidity with anxiety, somatoform and depressive disorders such as in Menière’s disease (38–48%), vestibular migraine 49%) and vestibular paroxysmia 51%) [% 1, 7–9–97–9. Th% and vesThe vestibular and fear/anxiety networks can be artificially stimulated in healthy volunteers to allow their examination in an experimental brain imaging setting. For vestibular stimulation, caloric, galvanic or sound-induced otolith stimulation are used inside the scanner. The central vestibular network in humans identified by earlier brain imaging studies runs from the vestibular brainstem nuclei via the posterolateral and centromedial thalamus to parietotemporal cortex areas . ItA close interconnection between the neural circuits of vestibular and anxiety systems has been postulated before , 5, but In the current study, we aimed to statistically overlap the neural substrates processing fear conditioning and vestibular stimulation, thereby confirming theoretical considerations derived from patient and animal studies. In a first step, we applied seed-based d-Mapping (SDM) on functional mapping studies in healthy volunteers investigating vestibular stimulation. The same SDM approach had been adopted for calculating meta-analytic data on fMRI studies applying fear conditioning that were provided by Fullana et al. . IncludiA comprehensive literature search using PubMed was conducted for peer-reviewed fMRI studies on vestibular stimulation until September 3rd, 2021. The search terms were “vestibular cortex” OR “vestibular stimulation” OR “caloric stimulation” OR “galvanic stimulation” AND human AND fMRI”. Additionally, we checked the reference sections of published articles, particularly the two existing activation likelihood estimation (ALE) meta-analyses , 13 idenFinally, we were able to collect imaging results from 10 independent fMRI studies using vestibular stimulation with 187 healthy adult participants   [Functional activation differences between the stimulation of the vestibular system and the control (rest) condition were analyzed using “Seed-based d-Mapping-Permutation of Subject Images (Sdm-Psi)”, version 6.21 (ect.com) . In contect.com) , this meect.com) . If onlyect.com) . These sect.com) .p < 0.05. MNI coordinates of the outcome files were checked and specified with the “Anatomy” toolbox .We used the Sdm-Psi pipeline with default parameter settings. After preprocessing, the calculated peak of one original dataset differed from the reported peak in the respective paper, so that instead of the statistical image, the reported peak information was included to the analysis. Our analysis thus comprised seven original statistical images , 34–39 as. 2.2b, ) of Statz value, but rather from the meta-analyses’ statistical significance .To assess the brain regions of common activations of vestibular stimulation and fear conditioning, we conservatively selected the voxels that showed statistical significance in both the vestibular and the fear conditioning meta-analysis, while we discarded voxels that showed statistical significance in only one of the meta-analyses. The statistical significance was not derived from the z values, we conservatively assigned each voxel the lowest z value between both meta-analyses . For instance, if in a given voxel, the z value was 3.2 in the vestibular meta-analysis and 3.7 in the fear conditioning meta-analysis, we would use 3.2 for the conjunction analysis. We thus provide a map of the minimum effects across meta-analyses: for each voxel, the z value in the different meta-analyses is at least as high as the z value of this map.To create the map of Visualization of activation maps was performed using MRICroGL .The brain regions demonstrating significant peak areas of high concordance during activation of the vestibular network showed the bilateral insula and adjacent structures, right Heschl’s gyrus (A1), the right temporal pole, putamen, thalamus, right amygdala, dorsolateral prefrontal cortex (DLPFC), left orbitofrontal cortex (OFC), cingulate cortex (CC), supplementary motor area (SMA), premotor cortex (PMC), M1, S1, S2, supramarginal gyrus, inferior parietal lobule (IPL), superior parietal lobule (SPL), cerebellum , and ponto-mesencephalic brainstem with inferior and superior colliculi  and left anterior cingulate cortex . A complete table showing all significant coordinates is added to the Supplemental Material (Supplementary Table 1).Peak areas of high concordance of deactivation under vestibular stimulation was evident in a cluster (1375 voxels) in the bilateral middle orbital gyrus  and no evidence of potential publication bias (Egger’s test: 6 out of 44 significant with p < 0.05) in the main results (Supplementary Table 1).Our additional analyses indicated that there was low heterogeneity , the bilateral posterior insula , the bilateral S2 (OP1 and OP3), and the left superior temporal gyrus  .Applying a voxel-based meta-analysis across 10 functional imaging studies during vestibular stimulation, we identified a distributed network comprising the bilateral insula and adjacent structures, Heschl’s gyrus and superior temporal lobe, anterior and medial thalamus, right superior amygdala, frontal lobe structures , superior and inferior parietal lobe and the intraparietal sulcus, mesencephalic brainstem and cerebellum (vermis and anterior hemisphere). This is in agreement with several earlier human imaging studies conducted by various groups , 13, 25.In the following the most relevant areas of a network overlap will be discussed with respect to their possible functional implications. Three main findings regard the insula: (A) the entire insula in both hemispheres was mapped demonstrating significant activation during vestibular stimulation, (B) the conjunction of vestibular and fear conditioning stimulation revealed an overlap of activation in the anterior insula bilaterally, (C) the posterior insula showed concordance of increased activation during vestibular stimulation but decreased activation during fear conditioning. Overall, the insula is called the hub of the salience network integrating incoming stimuli of all modalities with the internal state of the body and mind  , 45. TheConvergent activation in S2 (OP1) indicated an important role in both hemispheres not only for vestibular processing , 13, 15,The role of the amygdala during fear conditioning has been the subject of much discussion. Since amygdala activation is stronger during the first part of fear conditioning experiments , and alsHigh convergence was also evident in the dorsal anterior cingulate cortex for both vestibular and fear conditioning, compatible with the major involvement of this region in emotion by connections of the anterior part to the orbitofrontal cortex and the amygdala, its tight interconnection with the anterior insula , but alsWith regard to the overlap between vestibular and fear processing, we also found convergence in the antero-medial thalamus, anterior thalamic projections, and the striatum . These thalamic areas are interconnected with areas of the prefrontal and the temporal lobe, which showed also significant convergent activation. Both fear and vestibular stimulation provide relevant behavioral input resulting in an increased arousal, which is processed in the thalamus . In shorConvergence for vestibular stimulation and fear conditioning was detected in the cerebellar vermis and posterior cerebellar hemisphere (Larsell’s VI), but not in sensorimotor areas of the anterior cerebellar hemisphere (Larsell HV). Posterior superior cerebellar activation has been shown to be involved in fear conditioning , and alsThe current meta-analysis of vestibular stimulation studies exhibited convergent bilateral activation of the inferior colliculi (IC) and the superior colliculi, functionally most relevant structures for eye-, head- and body orientation and motor behavior in space and largely dependent on life-threatening emotional processes. The IC is a center for integration and analysis of various auditory features with ascending and descending pathways in the brainstem transmitting auditory information to the ipsilateral thalamus and cerebral cortex . For 3D-The superior colliculus is a multisensory nucleus with the major input from the retina as well as auditory and somatosensory receptors to mediate the orientation of the head and senses toward targets of interest to analyze (sensory input) and control (motor output) gaze as well as ears, head, and body in space. This synkinesis of coordinated orientation movements is critical for survival. In a threatening situation, the superior colliculus elicits a reflex-like orientation and defense response in animals (for review see: –78). AftBeyond this, anxiety and vegetative dysregulation are not only symptoms of acute vestibular vertigo syndromes but can also be the major provoking stimuli of frequent dizziness/vertigo syndromes like functional phobic postural dizziness (or PPPD) , 81 or vThere are a number of limitations of the current study: first, we calculated the overlap of two meta-analyses that had different sample sizes and thus different power, so that the meta-analysis with the smaller sample (vestibular stimulation) may have detected fewer regions of convergence than fear conditioning and accordingly reduced the overlap. It is worth reminding here that the two meta-analyses were independent, i.e., they were conducted with different participants at different time points. Second, every meta-analysis can just be as exact as the studies selected as their basis. This restricts conclusions on brainstem activation , the modeling of amygdala response and other functional activations sensitive to timing, but also the application of cluster-based statistical thresholding. An exact localization of processes in the brainstem has therefore to be performed in fMRI studies optimized for high brainstem resolution handling specific problems, such as liquor pulsation, high susceptibility artifacts and spatial normalization problems when an MNI brain normalization is applied . ThEarlier electrophysiological and tracer studies in animals and fMRI/ PET imaging in humans have established the concept of complex bilateral cerebral networks for the vestibular Regions exhibiting high overlap in vestibular stimulation and fear conditioning include the anterior insula and anterior cingulate sulcus, whose above discussed structural and functional features are essential for emotional interoception. The posterior cingulate sulcus and superior colliculus mediate multisensory spatial orientation and memory. The antero-medial thalamus with its connection to the prefrontal and temporal lobes and midbrain colliculi is involved in an increased arousal. This is relevant for avoidance of obstacles or other potentially dangerous situations during locomotion in unfamiliar terrains. The superior colliculus is the major hub for reflexive coordinated eye, head, body orientation movements, for instance, recognition and avoidance of unexpected threatening stimuli (fight or fly). The posterior insula and S2 are special in that the contrast for vestibular activations and fear conditioning deactivations resulted in a deactivation of these areas, possibly involved in weakening distressing anxiety and vegetative effects of excessive vestibular stimulations or acute vertigo disorders.Supplementary file1 (TIF 2140 kb)Supplementary file2 (PDF 95 kb)Supplementary file3 (PDF 69 kb)Below is the link to the electronic supplementary material.


Cellular force transmission across a hierarchy of molecular switchers is central to mechanobiological responses. However, current cellular force microscopies suffer from low throughput and resolution. Here we introduce and train a generative adversarial network (GAN) to paint out traction force maps of cell monolayers with high fidelity to the experimental traction force microscopy (TFM). The GAN analyzes traction force maps as an image-to-image translation problem, where its generative and discriminative neural networks are simultaneously cross-trained by hybrid experimental and numerical datasets. In addition to capturing the colony-size and substrate-stiffness dependent traction force maps, the trained GAN predicts asymmetric traction force patterns for multicellular monolayers seeding on substrates with stiffness gradient, implicating collective durotaxis. Further, the neural network can extract experimentally inaccessible, the hidden relationship between substrate stiffness and cell contractility, which underlies cellular mechanotransduction. Trained solely on datasets for epithelial cells, the GAN can be extrapolated to other contractile cell types using only a single scaling factor. The digital TFM serves as a high-throughput tool for mapping out cellular forces of cell monolayers and paves the way toward data-driven discoveries in cell mechanobiology. Much has been known about mechanical force transduction that entangles with biochemical signaling in cell-cell and cell-extracellular matrix communications, directing long-range multicellular morphogenesis7, wound healing9, and cancer metastasis11. However, the significance of mechanical force transduction in cellular mechanobiology is underserved by the lack of reliable, high-throughput tools for cellular force measurements14. Traction force microscopy (TFM) has been widely used to measure the pulling force by focal adhesion points17. The obtained traction force map is a prerequisite for monolayer stress microscopy (MSM)19 and intercellular tension microscopy (ITM)22. However, TFM is of low throughput and labor intensive23 and suffers from decreasing-to-vanishing resolution as the stiffness of the extracellular matrix (ECM) goes above 50kPa24. The lack of a reliable, high-throughput tool for cellular force measurements has critically hindered our understanding of cellular mechanobiology.The remarkable ability of cells to sense, respond, and adapt to mechanical forces is essential to cellular functions25. Here, we develop a generative adversarial network (GAN)26 to learn and predict the traction force distribution of cell monolayers seeding on a flat surface. Taking cell phase contrast images as the input, the GAN analyzes traction force maps as an image-to-image translation problem, where its generative and discriminative neural networks are cross-trained toward a converged solution. As experimental TFM yields insufficient experimental data required for neural network training and testing, we here resort to a recently developed high-throughput continuum model to generate numerical data20. Upon optimization and training with the hybrid experimental and numerical datasets, our neural network can perform diverse tasks, including forward prediction of the substrate-stiffness and colony-size dependent traction force maps and inverse delineation of the hidden relationship between cell contractility and substrate stiffness. Furthermore, our ML model predicts traction force concentration at the stiff side when seeding cells on a substrate with stiffness gradient, which implies collective durotaxis. While the GAN is trained by datasets exclusively for epithelial cells, it can be conveniently extrapolated to other contractile cell types by only a single scaling factor. Compared with conventional TFM and physics-based modeling, our digital TFM (DTFM) is highly efficient and versatile to be further adapted to other image-image translation tasks in cell mechanobiology.Machine-learning (ML) methods have revolutionized pattern recognition and generation with unprecedented accuracy and efficiency11. For two-dimensional (2D) TFM that measures the tangential pulling force, i.e., traction on flat substrates16, fluorescent beads are embedded into a soft substrate  to track the traction-induced displacement through an optical microscope,27 in reference to the traction-free condition in which cells are detached off from the substrate. The measured displacement field along with the boundary conditions furnishes an inverse elasticity problem for traction force calculation24. Using the TFM-reconstructed traction force distribution as a force boundary condition, the stress in the cell body, modeled as a thin monolayer,28 can be further determined by monolayer stress microscopy (MSM). The traction force profile indicates focal adhesion distribution29, while the direction of the first principal stress of the cell monolayer infers stress-fiber orientation30. For migrating cells, TFM can be applied at different time points, thereby obtaining time-varying traction force maps32.When seeded on a substrate, migrating cells develop focal adhesion points that pull and deform the substrate. The deformation depends on the pulling force of the cells as well as the mechanical properties of the substrate, i.e., its stiffness and Poisson’s ratioExtended data Fig. 1). Preparing a large database (103~104 traction force maps) through experimental TFM is undoubtedly very costly, owing to its low-throughput characteristic. To meet this challenge, we here generate training data by invoking our previously developed continuum model20. The continuum model assumes that the traction force distribution of a cell monolayer is determined by its current configuration33, and imposes the chemomechanical balance laws on the cell-substrate system (Supplementary Information). The continuum model simultaneously yields focal adhesion distribution, monolayer stress distribution, and traction force maps. The predicted traction force maps and monolayer stress distributions  agree very well with TFM and MSM measurements, respectively.20Training an ML model on high dimensional spaces entails a large dataset for converged model performance. For each cell type, we have no more than 100 experimental traction force maps available up to date, with epithelial cells being the mostly characterized cell type . The numerical results constitute the main part of the dataset, in addition to the experimental traction force maps from our own group and others. To complement the dataset, we also performed the standard data augmentation algorithm (Supplementary Information) on the limited experimental data. The final dataset includes ~8000 numerical simulations and ~600 experimental TFM measurements.33, determined by cell geometry, substrate stiffness, and cell type, which constitute the training data of our ML model. The input cell boundary Here we regard traction force as a configurational forceCombining experimental measurements and continuum mechanics modeling, we sample the input space of 34 in computer vision technology. Inspired by the recent progress in image generation35 and style transfer36, we designed a generative adversarial network (GAN) to extract the underlying distribution patterns of traction force. A GAN consists of a generative (generator) and a discriminative (discriminator) neural network, where the generator and the discriminator compete and evolve together to reach a final converged image. Upon training, the generator gains increasing ability to generate artificial data that can effectively fool the discriminator. When the discriminator can no longer effectively distinguish the difference between the ground-truth data and artificial data generated by the generator, the cross-training converges. As shown in 37, a classical convolutional neural network (CNN) widely applied in biomedical image segmentation tasks, and our discriminator is composed of a CNN linked to a fully connected neural network. The loss function For task I, we recast the prediction of traction force maps from given cell geometry as the image-image translation problemt images , while tExtended data Fig. 3). Above two features of traction force distribution can also be clearly observed from the intermediate feature maps  from the trained generator. We then define the average pixelwise error by As shown in  size R‾ , but rele R‾ , inversely predicting hidden correlations using traction force map Cells sense and adapt to their mechanical environments by operating their contractile machinery at different levels through mechanotransduction learned . Similarfness ES . This in49, despite cell-type dependent contractility 50, Hela51, MDCK22, and Osteosarcoma52 cell lines) by a constant Contractile cells of different types share similar mechano-biochemical feedback loops in traction force generationurements –B. As exIn summary, the GAN, trained by hybrid experimental and numerical datasets, can paint out high-fidelity traction force maps using only cell contours as the input. As the continuum model involves multi-field coupled partial differential equations (PDEs), our ML framework serves as an efficient PDE solver. In addition to predicting substrate-stiffness and colony-size dependent traction force maps, the neural network can unveil the hidden relationship between substrate stiffness and cell contractility, which is experimentally inaccessible but at the heart of mechanobiology. Without further modification of neural network architecture, the ML model predicts asymmetric traction force distribution in accordance with substrate stiffness gradient, demonstrating its power of predicting collective durotaxis. Furthermore, trained by data only for epithelial cells, our ML model can be extended to other contractile cell types, by only a single scaling factor associated with each cell type. Taken together, the GAN presents a powerful DTFM for estimating the traction force maps of cell monolayers.54, multicellular morphogenesis55, and cancer metastasis42, etc.Our DTFM can be employed to predict the time-varying traction forces for migrating cells. This extension is rather straightforward as cell contour is the only required input for the DTFM and is routinely available in almost all cell biology labs. As traction force distribution is a prerequisite for measurements of cell monolayer stress and intercellular tension, the established DTFM enables convenient development of digital MSM and IFM, making it a complete toolset for extra-, intra- and inter-cellular force measurements. Such digital force microscopies support new discoveries with unprecedented pace and precision with regard to the central role of mechanical forces in complex mechanobiochemical processes, such as collective cell migrationTo complement the TFM measurements, we construct a database of cell profiles and corresponding traction forces using continuum simulations (Supplementary Information). To generate a sufficiently extensive dataset that can cover the latent space of 2D cell profiles, we develop an algorithm to effectively control the regularity and curvature of randomly generated cell geometries. The algorithm uses a simple descriptor vector 20, where we consider the chemomechanical thermodynamics equilibrium of a cell monolayer adhering to a soft substrate. Beginning from a Helmholtz free energy functional incorporating the elastic, edge, and interfacial effects of the cell-substrate system, along with the biochemical signaling and diffusion of the adhesion molecules, we analyze the stable state by minimizing the total free energy with respect to the displacement field and the concentration of adhesion molecules. See Supplementary Information for details.Our continuum model for cell traction forces is based on ReferenceWe derive the weak form of governing equations (Supplementary Information) and implement the corresponding high-throughput simulations by Java 11.0 and COMSOL Multiphysics package (Version 5.5). The input cell geometries are discretized by quadradic triangular elements with appropriate size balancing the computational cost and simulation precision. Stationary solver with the Newton-Raphson algorithm is applied to solve the nonlinear boundary value problem. The output data from COMSOL Multiphysics is postprocessed by Python scripts to fit the format requirement of machine learning libraries.2. The stiffness of the substrate is controlled by adjusting the concentrations of acrylamide and bis-acrylamide. Prior to cell seeding, we coat the top surface of the substrate with fibronectin. To track the displacements induced by cell traction, we embed fluorescent beads in a single plane beneath the top surface of the substrate. The seeded HCT-8 cells are then cultivated for 24–72 hours, until the cell monolayer has sufficiently adhered, spread, and grown into multicellular colonies of varying sizes. To measure the monolayer thickness, we take three-dimensional images of the cell colonies using a laser-scanning confocal fluorescence microscope . Standard TFM is applied then solve the inverse elasticity problem for the cell traction forces. Further details on this experimental setup can be found in Supplementary Information.We seed HCT-8 cells onto a soft substrate made of PAA hydrogels at a density of 2000cells/cm37, which is an encoder-decoder architecture with a symmetric input and output format. The basic building blocks encoder and decoder of the generator consist of several convolution/max pooling operators and a nonlinear ReLU activation function. The discriminator shares a similar structure to the encoder of the generator. The GAN is implemented based on PyTorch56, a Python-based deep learning library. We set the training parameter as follows: 200 epochs to stop training, ADAM optimizer with the learning rate We design the generator as an adapted U-Net