Noninvasive modulation of human corticostriatal activity.

Corticostriatal activity is an appealing target for nonpharmacological treatments of brain disorders. In humans, corticostriatal activity may be modulated with noninvasive brain stimulation (NIBS). However, a NIBS protocol with a sound neuroimaging measure demonstrating a change in corticostriatal activity is currently lacking. Here, we combine transcranial static magnetic field stimulation (tSMS) with resting-state functional MRI (fMRI). We first present and validate the ISAAC analysis, a well-principled framework that disambiguates functional connectivity between regions from local activity within regions. All measures of the framework suggested that the region along the medial cortex displaying greater functional connectivity with the striatum is the supplementary motor area (SMA), where we applied tSMS. We then use a data-driven version of the framework to show that tSMS of the SMA modulates the local activity in the SMA proper, in the adjacent sensorimotor cortex, and in the motor striatum. We finally use a model-driven version of the framework to clarify that the tSMS-induced modulation of striatal activity can be primarily explained by a change in the shared activity between the modulated motor cortical areas and the motor striatum. These results suggest that corticostriatal activity can be targeted, monitored, and modulated noninvasively in humans.

Unilateral focused ultrasound subthalamotomy in early Parkinson's disease: a pilot study.

BACKGROUND: Unilateral focused ultrasound subthalamotomy (FUS-STN) improves motor features of Parkinson's disease (PD) in moderately advanced patients. The less invasive nature of FUS makes its early application in PD feasible. We aim to assess the safety and efficacy of unilateral FUS-STN in patients with PD of less than 5 years from diagnosis (early PD). METHODS: Prospective, open-label study. Eligible patients with early PD had highly asymmetrical cardinal features. The primary outcome was safety, defined as treatment-related adverse events at 6 months. Secondary outcomes included efficacy, assessed as motor improvement in the Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), motor fluctuations, non-motor symptoms, daily living activities, quality of life, medication and patients' impression of change. RESULTS: Twelve patients with PD (median age 52.0 (IQR 49.8-55.3) years, median time from diagnosis 3.0 (2.1-3.9) years) underwent unilateral FUS-STN. Within 2 weeks after treatment, five patients developed dyskinesia on the treated side, all resolved after levodopa dose adjustment. One patient developed mild contralateral motor weakness which fully resolved in 4 weeks. One patient developed dystonic foot and another hand and foot dystonia. The latter impaired gait and became functionally disabling initially. Both cases were well controlled with botulinum toxin injections. The off-medication motor MDS-UPDRS score for the treated side improved at 12 months by 68.7% (from 14.5 to 4.0, p=0.002), and the total motor MDS-UPDRS improved by 49.0% (from 26.5 to 13.0, p=0.002). Eleven patients (92%) reported global improvement 12 months after treatment. CONCLUSION: Unilateral FUS-STN may be safe and effective to treat motor manifestations in patients with early PD. A larger confirmatory trial is warranted. TRIAL REGISTRATION NUMBER: NCT04692116.

Nigrostriatal blood-brain barrier opening in Parkinson's disease.

BACKGROUND: The nigrostriatal system is especially vulnerable to neurodegeneration in Parkinson's disease (PD) and the blood-brain barrier (BBB) is a limiting factor for delivery of therapeutic agents to the brain. This pilot study aimed to demonstrate safety, feasibility and tissue penetration (by 18F-Choline-positron emission tomography (PET)) of MR-guided focused ultrasound (MRgFUS) simultaneous BBB opening (BBB-O) in the substantia nigra (SN) and putamen in PD. METHODS: Three patients underwent MRgFUS for midbrain and putamen BBB-O. Patients were evaluated clinically and underwent brain MRI with gadolinium (baseline, 24 hours, 14 days and 3 months postprocedure). In two patients, BBB-O was repeated after 2-3 weeks, and 18F-Choline-PET was performed immediately after. RESULTS: The right SN and putamen were simultaneously opened unilaterally in 3 patients once and the left SN in 1 patient in a different session. No severe clinical or neuroimaging adverse events developed in any patient. 18F-Choline-PET uptake was enhanced in the targeted SN and putamen regions. CONCLUSION: BBB-O of the nigrostriatal system is a feasible and well-tolerated approach in patients with PD. 18F-Choline-PET uptake indicates penetration into the parenchyma after BBB-O, which suggests that the opening is functionally effective. This minimally invasive technique could facilitate delivery of putative neurorestorative molecules to brain regions vulnerable to neurodegeneration.

Randomized Trial of Focused Ultrasound Subthalamotomy for Parkinson's Disease.

BACKGROUND: The subthalamic nucleus is the preferred neurosurgical target for deep-brain stimulation to treat cardinal motor features of Parkinson's disease. Focused ultrasound is an imaging-guided method for creating therapeutic lesions in deep-brain structures, including the subthalamic nucleus. METHODS: We randomly assigned, in a 2:1 ratio, patients with markedly asymmetric Parkinson's disease who had motor signs not fully controlled by medication or who were ineligible for deep-brain stimulation surgery to undergo focused ultrasound subthalamotomy on the side opposite their main motor signs or a sham procedure. The primary efficacy outcome was the between-group difference in the change from baseline to 4 months in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor score (i.e., part III) for the more affected body side (range, 0 to 44, with higher scores indicating worse parkinsonism) in the off-medication state. The primary safety outcome (procedure-related complications) was assessed at 4 months. RESULTS: Among 40 enrolled patients, 27 were assigned to focused ultrasound subthalamotomy (active treatment) and 13 to the sham procedure (control). The mean MDS-UPDRS III score for the more affected side decreased from 19.9 at baseline to 9.9 at 4 months in the active-treatment group (least-squares mean difference, 9.8 points; 95% confidence interval [CI], 8.6 to 11.1) and from 18.7 to 17.1 in the control group (least-squares mean difference, 1.7 points; 95% CI, 0.0 to 3.5); the between-group difference was 8.1 points (95% CI, 6.0 to 10.3; P<0.001). Adverse events in the active-treatment group were dyskinesia in the off-medication state in 6 patients and in the on-medication state in 6, which persisted in 3 and 1, respectively, at 4 months; weakness on the treated side in 5 patients, which persisted in 2 at 4 months; speech disturbance in 15 patients, which persisted in 3 at 4 months; facial weakness in 3 patients, which persisted in 1 at 4 months; and gait disturbance in 13 patients, which persisted in 2 at 4 months. In 6 patients in the active-treatment group, some of these deficits were present at 12 months. CONCLUSIONS: Focused ultrasound subthalamotomy in one hemisphere improved motor features of Parkinson's disease in selected patients with asymmetric signs. Adverse events included speech and gait disturbances, weakness on the treated side, and dyskinesia. (Funded by Insightec and others; ClinicalTrials.gov number, NCT03454425.).

Onset pattern of nigrostriatal denervation in early Parkinson's disease.

The striatal dopaminergic deficit in Parkinson's disease exhibits a typical pattern, extending from the caudal and dorsal putamen at onset to its more rostral region as the disease progresses. Clinically, upper-limb onset of cardinal motor features is the rule. Thus, according to current understanding of striatal somatotopy (i.e. the lower limb is dorsal to the upper limb) the assumed pattern of early dorsal striatal dopaminergic denervation in Parkinson's disease does not fit with an upper-limb onset. We have examined the topography of putaminal denervation in a cohort of 23 recently diagnosed de novo Parkinson's disease patients and 19 age-/gender-matched healthy subjects assessed clinically and by 18F-DOPA PET; 15 patients were re-assessed after 2 years. There was a net upper-limb predominance of motor features at onset. Caudal denervation of the putamen was confirmed in both the more- and less-affected hemispheres and corresponding hemibodies. Spatial covariance analysis of the most affected hemisphere revealed a pattern of 18F-DOPA uptake rate deficit that suggested focal dopamine loss starting in the posterolateral and intermediate putamen. Functional MRI group-activation maps during a self-paced motor task were used to represent the somatotopy of the putamen and were then used to characterize the decline in 18F-DOPA uptake rate in the upper- and lower-limb territories. This showed a predominant decrement in both hemispheres, which correlated significantly with severity of bradykinesia. A more detailed spatial analysis revealed a dorsoventral linear gradient of 18F-DOPA uptake rate in Parkinson's disease patients, with the highest putamen denervation in the caudal intermediate subregion (dorsoventral plane) compared to healthy subjects. The latter area coincides with the functional representation of the upper limb. Clinical motor assessment at 2-year follow-up showed modest worsening of parkinsonism in the primarily affected side and more noticeable increases in the upper limb in the less-affected side. Concomitantly, 18F-DOPA uptake rate in the less-affected putamen mimicked that recognized on the most-affected side. Our findings suggest that early dopaminergic denervation in Parkinson's disease follows a somatotopically related pattern, starting with the upper-limb representation in the putamen and progressing over a 2-year period in the less-affected hemisphere. These changes correlate well with the clinical presentation and evolution of motor features. Recognition of a precise somatotopic onset of nigrostriatal denervation may help to better understand the onset and progression of dopaminergic neurodegeneration in Parkinson's disease and eventually monitor the impact of putative therapies.

Cerebral metabolic pattern associated with progressive parkinsonism in non-human primates reveals early cortical hypometabolism.

Dopaminergic denervation in patients with Parkinson's disease is associated with changes in brain metabolism. Cerebral in-vivo mapping of glucose metabolism has been studied in severe stable parkinsonian monkeys, but data on brain metabolic changes in early stages of dopaminergic depletion of this model is lacking. Here, we report cerebral metabolic changes associated with progressive nigrostriatal lesion in the pre-symptomatic and symptomatic stages of the progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson's Disease. Monkeys (Macaca fascicularis) received MPTP injections biweekly to induce progressive grades of dopamine depletion. Monkeys were sorted according to motor scale assessments in control, asymptomatic, recovered, mild, and severe parkinsonian groups. Dopaminergic depletion in the striatum and cerebral metabolic patterns across groups were studied in vivo by positron emission tomography (PET) using monoaminergic ([11C]-dihydrotetrabenazine; 11C-DTBZ) and metabolic (2-[18F]-fluoro-2-deoxy-d-glucose; 18F-FDG) radiotracers. 11C-DTBZ-PET analysis showed progressive decrease of binding potential values in the striatum of monkeys throughout MPTP administration and the development of parkinsonian signs. 18F-FDG analysis in asymptomatic and recovered animals showed significant hypometabolism in temporal and parietal areas of the cerebral cortex in association with moderate dopaminergic nigrostriatal depletion. Cortical hypometabolism extended to involve a larger area in mild parkinsonian monkeys, which also exhibited hypermetabolism in the globus pallidum pars interna and cerebellum. In severe parkinsonian monkeys, cortical hypometabolism extended further to lateral-frontal cortices and hypermetabolism also ensued in the thalamus and cerebellum. Unbiased histological quantification of neurons in Brodmann's area 7 in the parietal cortex did not reveal neuron loss in parkinsonian monkeys versus controls. Early dopaminergic nigrostriatal depletion is associated with cortical, mainly temporo-parietal hypometabolism unrelated to neuron loss. These findings, together with recent evidence from Parkinson's Disease patients, suggest that early cortical hypometabolism may be associated and driven by subcortical changes that need to be evaluated appropriately. Altogether, these findings could be relevant when potential disease modifying therapies become available.

Functional Topography of the Human Subthalamic Nucleus: Relevance for Subthalamotomy in Parkinson's Disease.

BACKGROUND: The subthalamic nucleus (STN) is considered a key structure in motor, behavioral, and emotional control. Although identification of the functional topography of the STN has therapeutic implications in the treatment of the motor features of Parkinson's disease (PD), the details of its functional and somatotopic organization in humans are not well understood. OBJECTIVE: The aim of this study was to characterize the functional organization of the STN and its correlation with the motor outcomes induced by subthalamotomy. METHODS: We used diffusion-weighted imaging to assess STN connectivity patterns in 23 healthy control subjects and 86 patients with PD, of whom 39 received unilateral subthalamotomy. Analytical tractography was used to reconstruct structural cortico-subthalamic connectivity. A diffusion-weighted imaging/functional magnetic resonance imaging-driven somatotopic parcellation of the STN was defined to delineate the representation of the upper and lower limb in the STN. RESULTS: We confirmed a connectional gradient to sensorimotor, supplementary-motor, associative, and limbic cortical regions, spanning from posterior-dorsal-lateral to anterior-ventral-medial portions of the STN, with intermediate overlapping zones. Functional magnetic resonance imaging-driven parcellation demonstrated dual segregation of motor cortico-subthalamic projections in humans. Moreover, the relationship between lesion topography and functional anatomy of the STN explains specific improvement in bradykinesia, rigidity, and tremor induced by subthalamotomy. CONCLUSIONS: Our results support an interplay between segregation and integration of cortico-subthalamic projections, suggesting the coexistence of parallel and convergent information processing. Identifying the functional topography of the STN will facilitate better definition of the optimal location for functional neurosurgical approaches, that is, electrode placement and lesion location, and improve specific cardinal features in PD. © 2021 International Parkinson and Movement Disorder Society.

Striatal Blood-Brain Barrier Opening in Parkinson's Disease Dementia: A Pilot Exploratory Study.

BACKGROUND: Parkinson's disease (PD) exhibits a high prevalence of dementia as disease severity and duration progress. Focused ultrasound (FUS) has been applied for transient blood-brain barrier (BBB) opening of cortical regions in neurodegenerative disorders. The striatum is a primary target for delivery of putative therapeutic agents in PD. OBJECTIVE: Here, we report a prospective, single-arm, nonrandomized, proof-of-concept, phase I clinical trial (NCT03608553 amended) in PD with dementia to test the safety and feasibility of striatal BBB opening in PD patients. METHODS: Seven PD patients with cognitive impairment were treated for BBB opening in the posterior putamen. This was performed in two sessions separated by 2 to 4 weeks, where the second session included bilateral putamina opening in 3 patients. Primary outcome measures included safety and feasibility of focal striatal BBB opening. Changes in motor and cognitive functions, magnetic resonance imaging (MRI), 18 F-fluorodopa (FDOPA), and ß-amyloid PET (positron emission tomography) images were determined. RESULTS: The procedure was feasible and well tolerated, with no serious adverse events. No neurologically relevant change in motor and cognitive (battery of neuropsychological tests) functions was recognized at follow-up. MRI revealed putamen BBB closing shortly after treatment (24 hours to 14 days) and ruled out hemorrhagic and ischemic lesions. There was a discrete but significant reduction in ß-amyloid uptake in the targeted region and no change in FDOPA PET. CONCLUSIONS: These initial results indicate that FUS-mediated striatal BBB opening is feasible and safe and therefore could become an effective tool to facilitate the delivery of putative neurorestorative molecules in PD. © 2022 International Parkinson and Movement Disorder Society.

Motor Onset Topography and Progression in Parkinson's Disease: the Upper Limb Is First.

OBJECTIVE: To define the motor onset and progression of Parkinson's disease (PD) in a prospective cohort of early unmedicated patients. METHODS: We enrolled a consecutive cohort of recently diagnosed (<18 months) PD patients with unilateral manifestations using age and gender-matched controls. The most affected body region was determined using various clinical standard metrics and objective quantitative kinematic measurements. Parkinson's Progression Markers Initiative data were used for external validation of the results. RESULTS: Twenty-five drug-naive patients and 21 controls were studied. Upper limbs were (92%) the most affected body region at onset as ascertained by patients' self-assessment, neurologists' impression, and Movement Disorders Society Unified Parkinson's Disease Rating Scale score. The upper limb (ie, hand) was the site of onset in 80% of patients. Motor features progressed to involve the lower limb but remained limited to the initially affected body side over a 2-year follow-up. Agreement among the different metrics (96%) confirmed focal upper limb predominant motor impairment at onset. The findings were confirmed by quantitative kinematic analyses and from a cohort of 34 similar patients from the Parkinson's Progression Markers Initiative database. CONCLUSIONS: Motor manifestations in PD start distally in one upper limb. The complexity of the motor repertoire and, consequently, the presumed larger dopaminergic striatal demand for maintaining skillful motor function in the upper limb, may contribute to greater vulnerability of dopaminergic striatal terminals. Recognition of this motor pattern could be used to monitor the evolution of nigrostriatal degeneration and the putative impact of therapies. © 2021 International Parkinson and Movement Disorder Society.

Magnetic resonance-guided focused ultrasound for movement disorders: clinical and neuroimaging advances.

PURPOSE OF REVIEW: To describe the path of technological developments that have led to the actual application of MRI-guided focused ultrasound in multiple neurological disorders and to update the more recent technical advances in the field. An insight into the latest clinical achievements in movement disorders will be provided, together with the neuroimaging advances for the screening, planning, and outcome evaluation. RECENT FINDINGS: Developments, such as phased array transducers and MRI guidance have allowed the use of focused ultrasound to successfully perform incisionless therapeutic ablation in deep brain structures. Although its indication through a thalamotomy has been approved for essential and parkinsonian tremor, it has also shown preliminary efficacy for other types of tremor, Parkinson's disease motor signs and neuropsychiatric disorders. In parallel, neuroradiological techniques have helped to improve treatment application and provided new evidence in terms of lesion topography, impact on distant structures and understanding of action mechanisms. SUMMARY: Neuroimaging developments have helped to increase successful applications of focused ultrasound as a minimally invasive ablative approach and to understand the mechanisms by which ablation of a certain brain region improves neurological disorders. The field is expanding rapidly and in the coming years it will transform functional neurosurgery.

Functional impact of subthalamotomy by magnetic resonance-guided focused ultrasound in Parkinson's disease: a hybrid PET/MR study of resting-state brain metabolism.

PURPOSE: Subthalamotomy using magnetic resonance-guided focused ultrasound (MRgFUS) has become a potential treatment option for the cardinal features of Parkinson's disease (PD). The purpose of this study was to evaluate the effects of MRgFUS-subthalamotomy on brain metabolism using different scale levels. METHODS: We studied resting-state glucose metabolism in eight PD patients before and after unilateral MRgFUS-subthalamotomy using hybrid [18F]FDG-PET/MR imaging. We used statistical nonparametric mapping (SnPM) to study regional metabolic changes following this treatment and also quantified whole-brain treatment-related changes in the expression of a spatial covariance-based Parkinson's disease-related metabolic brain pattern (PDRP). Modulation of regional and network activity was correlated with clinical improvement as measured by changes in Unified Parkinson's Disease Rating Scale (MDS-UPDRS) motor scores. RESULTS: After subthalamotomy, there was a significant reduction in FDG uptake in the subthalamic region, globus pallidus internus, motor and premotor cortical regions, and cingulate gyrus in the treated hemisphere, and the contralateral cerebellum (p < 0.001). Diffuse metabolic increase was found in the posterior parietal and occipital areas. Treatment also resulted in a significant decline in PDRP expression (p < 0.05), which correlated with clinical improvement in UPDRS motor scores (rho = 0.760; p = 0.002). CONCLUSIONS: MRgFUS-subthalamotomy induced metabolic alterations in distributed nodes of the motor, associative, and limbic circuits. Clinical improvement was associated with reduction in the PDRP expression. This treatment-induced modulation of the metabolic network is likely to mediate the clinical benefit achieved following MRgFUS-subthalamotomy.

Focused ultrasound thalamotomy for multiple sclerosis-associated tremor.

Multiple sclerosis (MS)-related tremor is frequent and can often be refractory to medical treatment, which makes it a potential source of major disability. Functional neurosurgery approaches such as thalamic deep brain stimulation (DBS) or radiofrequency thalamotomy are proven to be effective, but the application of invasive techniques in MS tremor has so far been limited. Magnetic resonance (MR)-guided focused ultrasound thalamotomy, which has already been approved for treating essential and parkinsonian tremor, provides a minimally invasive approach that could be useful in the management of MS tremor. We report for the first time a patient with medically refractory MS-associated tremor successfully treated by focused ultrasound thalamotomy.

Microstructural changes of the dentato-rubro-thalamic tract after transcranial MR guided focused ultrasound ablation of the posteroventral VIM in essential tremor.

Essential tremor is the most common movement disorder in adults. In patients who are not responsive to medical treatment, functional neurosurgery and, more recently, transcranial MR-guided focused ultrasound thalamotomy are considered effective therapeutic approaches. However, the structural brain changes following a thalamotomy that mediates the clinical improvement are still unclear. In here diffusion weighted images were acquired in a cohort of 24 essential tremor patients before and 3 months after unilateral transcranial MR-guided focused ultrasound thalamotomy targeting at the posteroventral part of the VIM. Microstructural changes along the DRTT were quantified by means of probabilistic tractography, and later related to the clinical improvement of the patients at 3-months and at 1-year after the intervention. In addition the changes along two neighboring tracts, that is, the corticospinal tract and the medial lemniscus, were assessed, as well as the relation between these changes and the presence of side effects. Thalamic lesions produced local and distant alterations along the trajectory of the DRTT, and each correlated with clinical improvement. Regarding side effects, gait imbalance after thalamotomy was associated with greater impact on the DRTT, whereas the presence of paresthesias was significantly related to a higher overlap between the lesion and the medial lemniscus. This work represents the largest series describing the microstructural changes following transcranial MR-guided focused ultrasound thalamotomy in essential tremor. These results suggest that clinical benefits are specific for the impact on the cerebello-thalamo-cortical pathway, thus reaffirming the potential of tractography to aid thalamotomy targeting.

Focused ultrasound in Parkinson's disease: A twofold path toward disease modification.

A major unmet need in Parkinson's disease (PD) is to slow the inexorable progression of neurodegeneration. Clinical trials that evaluated promising pharmacological strategies have repeatedly failed. Nonetheless, the advent of focused ultrasound provides new opportunities toward the goal of developing a safe and effective disease-modifying therapy for PD. Here we discuss the rationale, possible avenues, and challenges along this path, exploiting the potential of focused ultrasound for (1) performing focal thermal lesions to restore the basic basal ganglia abnormalities associated with dopamine depletion, and (2) transiently opening the blood-brain barrier for targeted delivery of therapeutic agents. First, the classic idea of excitotoxicity mediated by hyperactivity of the subthalamic nucleus suggests that focused ultrasound subthalamotomy may offer a clinically viable disease-modifying therapy in very-early PD. Second, the concept of retrograde nigrostriatal neurodegeneration, supported by our recent cortical pathogenic theory of PD, points toward the putamen as a principal site for focused ultrasound blood-brain barrier opening and targeted drug delivery. In principle, both therapeutic strategies-subthalamotomy and putaminal blood-brain barrier opening-could eventually be applied in the same patient. Clinical application is still a long road ahead; nevertheless, focused ultrasound may open a twofold path toward disease modification in PD. © 2019 International Parkinson and Movement Disorder Society.

Zero TE MRI applications to transcranial MR-guided focused ultrasound: Patient screening and treatment efficiency estimation.

BACKGROUND: The high acoustic impedance of the skull limits the performance of transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) therapy. Subject suitability screening is based on skull parameters estimated from computed tomography (CT) scans. PURPOSE: To assess the feasibility of screening for tcMRgFUS based on zero echo time (ZTE) MRI, and to explore the influence of measurable skull parameters in treatment performance. STUDY TYPE: Retrospective. POPULATION: Sixteen patients treated with tcMRgFUS thalamotomy for tremor. SEQUENCE: ZTE on a 3.0T GE scanner. ASSESSMENT: Baseline CT and ZTE images were processed to extract skull measures associated with treatment success: skull density ratio (SDR), skull thickness, and angle of incidence. Eight new metrics were proposed. CT and ZTE-based measures were compared. Each subject's energy-temperature curve was processed to extract a global estimate of efficiency and a measure of nonlinearity. These parameters were then correlated with the skull measures. STATISTICAL TESTS: Linear regression analysis to compare ZTE vs. CT-based measures, measures vs. efficiency, and measures vs. nonlinearity. Paired t-test to assess nonlinearity. RESULTS: CT and ZTE-based measures were significantly correlated (P < 0.01). In particular, classical metrics were robustly replicated (P < 0.001). The energy-temperature curves showed a nonlinear (logarithmic) relationship (P < 0.01). This nonlinearity was greater for thicker skulls (P < 0.01). Efficiency was correlated with skull thickness (P < 0.001) and SDR (P < 0.05). DATA CONCLUSION: The feasibility of ZTE-based screening has been proven, potentially making it possible to avoid ionizing radiation and the extra imaging session required for CT. The characterization of the influence that skull properties have on tcMRgFUS may serve to develop patient-specific heating models, potentially improving control over the treatment outcome. The relationship of skull thickness with efficiency and nonlinearity empowers the role of this metric in the definition of such models. In addition, the lower association of SDR with the energy-temperature curves emphasizes the need of revisiting this metric. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1583-1592.

Structural brain connectivity and cognitive ability differences: A multivariate distance matrix regression analysis.

Neuroimaging research involves analyses of huge amounts of biological data that might or might not be related with cognition. This relationship is usually approached using univariate methods, and, therefore, correction methods are mandatory for reducing false positives. Nevertheless, the probability of false negatives is also increased. Multivariate frameworks have been proposed for helping to alleviate this balance. Here we apply multivariate distance matrix regression for the simultaneous analysis of biological and cognitive data, namely, structural connections among 82 brain regions and several latent factors estimating cognitive performance. We tested whether cognitive differences predict distances among individuals regarding their connectivity pattern. Beginning with 3,321 connections among regions, the 36 edges better predicted by the individuals' cognitive scores were selected. Cognitive scores were related to connectivity distances in both the full (3,321) and reduced (36) connectivity patterns. The selected edges connect regions distributed across the entire brain and the network defined by these edges supports high-order cognitive processes such as (a) (fluid) executive control, (b) (crystallized) recognition, learning, and language processing, and (c) visuospatial processing. This multivariate study suggests that one widespread, but limited number, of regions in the human brain, supports high-level cognitive ability differences. Hum Brain Mapp 38:803-816, 2017. © 2016 Wiley Periodicals, Inc.

The road ahead to successful BBB opening and drug-delivery with focused ultrasound.

This review delves into the innovative technology of Blood-Brain Barrier (BBB) opening with low-intensity focused ultrasound in combination with microbubbles (LIFU-MB), a promising therapeutic modality aimed at enhancing drug delivery to the central nervous system (CNS). The BBB's selective permeability, while crucial for neuroprotection, significantly hampers the efficacy of pharmacological treatments for CNS disorders. LIFU-MB emerges as a non-invasive and localized method to transiently increase BBB permeability, facilitating the delivery of therapeutic molecules. Here, we review the procedural stages of LIFU-MB interventions, including planning and preparation, sonication, evaluation, and delivery, highlighting the technological diversity and methodological challenges encountered in current clinical applications. With an emphasis on safety and efficacy, we discuss the crucial aspects of ultrasound delivery, microbubble administration, acoustic feedback monitoring and assessment of BBB permeability. Finally, we explore the critical choices for effective BBB opening with LIFU-MB, focusing on selecting therapeutic agents, optimizing delivery methods, and timing for delivery. Overcoming existing barriers to integrate this technology into clinical practice could potentially revolutionize CNS drug delivery and treatment paradigms in the near future.

Neurovascular and immune factors of vulnerability of substantia nigra dopaminergic neurons in non-human primates.

Dopaminergic neurons in the ventral tier of the substantia nigra pars compacta (SNc) degenerate prominently in Parkinson's disease (PD), while those in the dorsal tier and ventral tegmental area are relatively spared. The factors determining why these neurons are more vulnerable than others are still unrevealed. Neuroinflammation and immune cell infiltration have been demonstrated to be a key feature of neurodegeneration in PD. However, the link between selective dopaminergic neuron vulnerability, glial and immune cell response, and vascularization and their interactions has not been deciphered. We aimed to investigate the contribution of glial cell activation and immune cell infiltration in the selective vulnerability of ventral dopaminergic neurons within the midbrain in a non-human primate model of PD. Structural characteristics of the vasculature within specific regions of the midbrain were also evaluated. Parkinsonian monkeys exhibited significant microglial and astroglial activation in the whole midbrain, but no major sub-regional differences were observed. Remarkably, the ventral substantia nigra was found to be typically more vascularized compared to other regions. This feature might play some role in making this region more susceptible to immune cell infiltration under pathological conditions, as greater infiltration of both T- and B- lymphocytes was observed in parkinsonian monkeys. Higher vascular density within the ventral region of the SNc may be a relevant factor for differential vulnerability of dopaminergic neurons in the midbrain. The increased infiltration of T- and B- cells in this region, alongside other molecules or toxins, may also contribute to the susceptibility of dopaminergic neurons in PD.