A Scoping Review of Focused Ultrasound Enhanced Drug Delivery for Across the Blood-Brain Barrier for Brain Tumors.

BACKGROUND AND OBJECTIVES: Previous mechanisms of opening the blood-brain barrier (BBB) created a hypertonic environment. Focused ultrasound (FUS) has recently been introduced as a means of controlled BBB opening. Here, we performed a scoping review to assess the advances in drug delivery across the BBB for treatment of brain tumors to identify advances and literature gaps. METHODS: A review of current literature was conducted through a MEDLINE search inclusive of articles on FUS, BBB, and brain tumor barrier, including human, modeling, and animal studies written in English. Using the Rayyan platform, 2 reviewers (J.P and C.Y) identified 967 publications. 224 were chosen to review after a title screen. Ultimately 98 were reviewed. The scoping review was designed to address the following questions: (1) What FUS technology improvements have been made to augment drug delivery for brain tumors? (2) What drug delivery improvements have occurred to ensure better uptake in the target tissue for brain tumors? RESULTS: Microbubbles (MB) with FUS are used for BBB opening (BBBO) through cavitation to increase its permeability. Drug delivery into the central nervous system can be combined with MB to enhance transport of therapeutic agents to target brain tissue resulting in suppression of tumor growth and prolonging survival rate, as well as reducing systemic toxicity and degradation rate. There is accumulating evidence demonstrating that drug delivery through BBBO with FUS-MB improves drug concentrations and provides a better impact on tumor growth and survival rates, compared with drug-only treatments. CONCLUSION: Here, we review the role of FUS in BBBO. Identified gaps in the literature include impact of tumor microenvironment and extracellular space, improved understanding and control of MB and drug delivery, further work on ideal pharmacologics for delivery, and clinical use.

Staged Bilateral MRI-Guided Focused Ultrasound Subthalamotomy for Parkinson Disease.

Importance: Unilateral magnetic resonance imaging (MRI)-guided focused ultrasound subthalamotomy (FUS-STN) improves cardinal motor features among patients with asymmetrical Parkinson disease (PD). The feasibility of bilateral FUS-STN is as yet unexplored. Objective: To assess the safety and effectiveness of staged bilateral FUS-STN to treat PD. Design, Setting, and Participants: This prospective, open-label, case series study was conducted between June 18, 2019, and November 7, 2023, at HM-CINAC, Puerta del Sur University Hospital, Madrid, Spain, and included 6 patients with PD who had been treated with unilateral FUS-STN contralateral to their most affected body side and whose parkinsonism on the untreated side had progressed and was not optimally controlled with medication. Intervention: Staged bilateral FUS-STN. Main Outcomes and Measures: Primary outcomes were assessed 6 months after the second treatment and included safety (incidence and severity of adverse events after second treatment) and effectiveness in terms of motor change (measured with the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III [MDS-UPDRS III]) in the off-medication state (ie, after at least 12 hours of antiparkinsonian drug withdrawal) compared with baseline (ie, prior to the first side ablation). Secondary outcomes included motor change in patients in the on-medication state (ie, after usual antiparkinsonian medication intake), motor complications (measured with the MDS-UPDRS IV), daily living activities (measured with the MDS-UPDRS I-II), quality of life (measured with the 39-item Parkinson's Disease Questionnaire), change in dopaminergic treatment, patient's global impression of change (measured with the Global Impression of Change [PGI-C] scale), and long-term (24-month) follow-up. Results: Of 45 patients previously treated with unilateral FUS-STN, 7 were lost to follow-up, and 4 were excluded due to adverse events. Of the remaining 34 patients, 6 (median age at first FUS-STN, 52.6 years [IQR, 49.0-57.3 years]; 3 women [50%]) experienced progression of parkinsonism on the untreated body side and were included. At the time of the first FUS-STN, patients' median duration of disease was 5.7 years (IQR, 4.7-7.3 years). The median time between procedures was 3.2 years (IQR, 1.9-3.5 years). After the second FUS-STN, 4 patients presented with contralateral choreic dyskinesia, which resolved by 3 months. Four patients developed speech disturbances, which gradually improved but remained in a mild form for 2 patients at 6 months; 1 patient experienced mild imbalance and dysphagia during the first week after treatment, which subsided by 3 months. No behavioral or cognitive disturbances were found on neuropsychological testing. For patients in the off-medication state, MDS-UPDRS III scores improved by 52.6% between baseline and 6 months after the second FUS-STN (from 37.5 [IQR, 34.2-40.0] to 20.5 [IQR, 8.7-24.0]; median difference, 23.0 [95% CI, 7.0-33.7]; P = .03). The second treated side improved by 64.3% (MDS-UPDRS III score, 17.0 [IQR, 16.0-19.5] prior to the second treatment vs 5.5 [IQR, 3.0-10.2]; median difference, 9.5 [95% CI, 3.2-17.7]; P = .02). After the second procedure, all self-reported PGI-C scores were positive. Conclusions: Findings of this pilot study suggest that staged bilateral FUS-STN was safe and effective for the treatment of PD, although mild but persistent speech-related adverse events were observed among a small number of patients.

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.

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.

Deep-brain stimulation of the human nucleus accumbens-medial septum enhances memory formation.

Deep-brain stimulation (DBS) is a potential novel treatment for memory dysfunction. Current attempts to enhance memory focus on stimulating human hippocampus or entorhinal cortex. However, an alternative strategy is to stimulate brain areas providing modulatory inputs to medial temporal memory-related structures, such as the nucleus accumbens (NAc), which is implicated in enhancing episodic memory encoding. Here, we show that NAc-DBS improves episodic and spatial memory in psychiatric patients. During stimulation, NAc-DBS increased the probability that infrequent (oddball) pictures would be subsequently recollected, relative to periods off stimulation. In a second experiment, NAc-DBS improved performance in a virtual path-integration task. An optimal electrode localization analysis revealed a locus spanning postero-medio-dorsal NAc and medial septum predictive of memory improvement across both tasks. Patient structural connectivity analyses, as well as NAc-DBS-evoked hemodynamic responses in a rat model, converge on a central role for NAc in a hippocampal-mesolimbic circuit regulating encoding into long-term memory. Thus, short-lived, phasic NAc electrical stimulation dynamically improved memory, establishing a critical on-line role for human NAc in episodic memory and providing an empirical basis for considering NAc-DBS in patients with loss of memory function.

Longitudinal assessment of social cognition in de novo Parkinson's disease patients and its relationship with dopaminergic innervation.

BACKGROUND: Social Cognition (SC) has been scarcely studied in Parkinson's disease (PD), and findings in early disease are controversial. SC encompasses different capacities such as facial emotion recognition (FER); Theory of Mind (ToM), the ability to understand other people's intentions (cognitive-ToM) and emotions (affective-ToM); and self-monitoring, the ability to regulate one's own behavior in social contexts. A relationship between dopaminergic deficit and SC in PD has been suggested. OBJECTIVES: To prospectively assess, over a two-year period, SC in newly diagnosed drug-naïve, cognitively normal and non-depressed PD patients. Furthermore, we aimed to evaluate the relationship between SC and Fluorodopa (Positron Emission Tomography) Ki uptake, which is a marker of dopaminergic depletion. METHODS: We compared SC performance between 25 de novo PD patients and 20 healthy controls (HC), and within-patients at baseline and two-year follow-up. The SC assessment included FER, ToM, as well as self-monitoring measures. The relationship between SC and dopaminergic innervation was also assessed in patients. RESULTS: SC scores did not differ between PD and HC groups at baseline, nor between baseline and follow-up evaluation in PD. A significant positive correlation between self-monitoring and Fluorodopa Ki uptake in the left pallidum in PD patients was found at baseline. At follow-up, ToM (stories) positively correlated with Fluorodopa Ki uptake in the right thalamus and the left putamen. CONCLUSION: SC appears to be preserved in de novo PD and remains stable in the short-term. Although more evidence is needed, our results support a relationship between dopamine innervation in subcortical regions and SC.

Transcranial ultrasound simulation with uncertainty estimation.

Transcranial ultrasound simulations are increasingly used to predict in situ exposure parameters for ultrasound therapies in the brain. However, there can be considerable uncertainty in estimating the acoustic medium properties of the skull and brain from computed tomography (CT) images. This paper shows how the resulting uncertainty in the simulated acoustic field can be predicted in a computationally efficient way using linear uncertainty propagation. Results for a representative transcranial simulation using a focused bowl transducer at 500 kHz show good agreement with unbiased uncertainty estimates obtained using Monte Carlo.

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.

BBB opening with focused ultrasound in nonhuman primates and Parkinson's disease patients: Targeted AAV vector delivery and PET imaging.

Intracerebral vector delivery in nonhuman primates has been a major challenge. We report successful blood-brain barrier opening and focal delivery of adeno-associated virus serotype 9 vectors into brain regions involved in Parkinson's disease using low-intensity focus ultrasound in adult macaque monkeys. Openings were well tolerated with generally no associated abnormal magnetic resonance imaging signals. Neuronal green fluorescent protein expression was observed specifically in regions with confirmed blood-brain barrier opening. Similar blood-brain barrier openings were safely demonstrated in three patients with Parkinson's disease. In these patients and in one monkey, blood-brain barrier opening was followed by 18F-Choline uptake in the putamen and midbrain regions based on positron emission tomography. This indicates focal and cellular binding of molecules that otherwise would not enter the brain parenchyma. The less-invasive nature of this methodology could facilitate focal viral vector delivery for gene therapy and might allow early and repeated interventions to treat neurodegenerative disorders.

Classical and Learned MR to Pseudo-CT Mappings for Accurate Transcranial Ultrasound Simulation.

Model-based treatment planning for transcranial ultrasound therapy typically involves mapping the acoustic properties of the skull from an X-ray computed tomography (CT) image of the head. Here, three methods for generating pseudo-CT (pCT) images from magnetic resonance (MR) images were compared as an alternative to CT. A convolutional neural network (U-Net) was trained on paired MR-CT images to generate pCT T images from either T1-weighted or zero-echo time (ZTE) MR images (denoted tCT and zCT, respectively). A direct mapping from ZTE to pCT was also implemented (denoted cCT). When comparing the pCT and ground-truth CT images for the test set, the mean absolute error was 133, 83, and 145 Hounsfield units (HU) across the whole head, and 398, 222, and 336 HU within the skull for the tCT, zCT, and cCT images, respectively. Ultrasound simulations were also performed using the generated pCT images and compared to simulations based on CT. An annular array transducer was used targeting the visual or motor cortex. The mean differences in the simulated focal pressure, focal position, and focal volume were 9.9%, 1.5 mm, and 15.1% for simulations based on the tCT images; 5.7%, 0.6 mm, and 5.7% for the zCT; and 6.7%, 0.9 mm, and 12.1% for the cCT. The improved results for images mapped from ZTE highlight the advantage of using imaging sequences, which improves the contrast of the skull bone. Overall, these results demonstrate that acoustic simulations based on MR images can give comparable accuracy to those based on CT.

Clinical trajectories and biomarkers for weight variability in early Parkinson's disease.

Unexplained weight changes that occur in Parkinson's disease (PD), are often neglected and remain a poorly understood non-motor feature in patients with PD. A specific 'Park-weight' phenotype with low body weight has been described, and our aim was to evaluate the clinical and prognostic trajectories and biomarkers of weight variability in PD. We evaluated body weight-related biomarkers in 405 de novo PD patients and 187 healthy controls (HC) over a 5-year follow-up period from the PPMI database. Body-weight variability was defined as intra-individual variability in body weight between visits. PD patients were categorized as weight losers, gainers, or patients with stable weight. The differential progression of motor and non-motor clinical variables between groups was explored using linear mixed-effects models. Finally, we estimated longitudinal changes in weight as a function of baseline and longitudinal striatal presynaptic dopaminergic transporter imaging. PD patients presented a greater weight variability compared to HC (p = 0.003). Patients who developed weight loss had lower CSF amyloid-beta 1-42 (p = 0.009) at baseline. In addition, patients with weight loss showed a faster cognitive decline (p = 0.001), whereas patients with weight gain showed a slower motor progression (p = 0.001), compared to patients with stable weight. Baseline right striatal denervation was a predictor of weight variability in both PD patients and HC (p < 0.001). Similarly, weight variability in PD patients was associated with the progression of right striatal denervation (p < 0.001). Weight variability and specifically weight loss are more frequent in PD compared to HC, and are associated with specific motor, non-motor and cognitive progression patterns. A greater CSF amyloid burden was present at baseline in patients with subsequent weight loss. Presynaptic dopaminergic imaging in the right striatum may serve as a predictor of future weight changes in PD and HC.

Neuroimaging signatures predicting motor improvement to focused ultrasound subthalamotomy in Parkinson's disease.

Subthalamotomy using transcranial magnetic resonance-guided focused ultrasound (tcMRgFUS) is a novel and promising treatment for Parkinson's Disease (PD). In this study, we investigate if baseline brain imaging features can be early predictors of tcMRgFUS-subthalamotomy efficacy, as well as which are the post-treatment brain changes associated with the clinical outcomes. Towards this aim, functional and structural neuroimaging and extensive clinical data from thirty-five PD patients enrolled in a double-blind tcMRgFUS-subthalamotomy clinical trial were analyzed. A multivariate cross-correlation analysis revealed that the baseline multimodal imaging data significantly explain (P < 0.005, FWE-corrected) the inter-individual variability in response to treatment. Most predictive features at baseline included neural fluctuations in distributed cortical regions and structural integrity in the putamen and parietal regions. Additionally, a similar multivariate analysis showed that the population variance in clinical improvements is significantly explained (P < 0.001, FWE-corrected) by a distributed network of concurrent functional and structural brain changes in frontotemporal, parietal, occipital, and cerebellar regions, as opposed to local changes in very specific brain regions. Overall, our findings reveal specific quantitative brain signatures highly predictive of tcMRgFUS-subthalamotomy responsiveness in PD. The unanticipated weight of a cortical-subcortical-cerebellar subnetwork in defining clinical outcome extends the current biological understanding of the mechanisms associated with clinical benefits.

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.

Static magnetic field stimulation over motor cortex modulates resting functional connectivity in humans.

Focal application of transcranial static magnetic field stimulation (tSMS) over the human motor cortex induces local changes in cortical excitability. Whether tSMS can also induce distant network effects, and how these local and distant effects may vary over time, is currently unknown. In this study, we applied 10 min tSMS over the left motor cortex of healthy subjects using a real/sham parallel design. To measure tSMS effects at the sensori-motor network level, we used resting-state fMRI. Real tSMS, but not sham, reduced functional connectivity within the stimulated sensori-motor network. This effect of tSMS showed time-dependency, returning to sham levels after the first 5 min of fMRI scanning. With 10 min real tSMS over the motor cortex we did not observe effects in other functional networks examined (default mode and visual system networks). In conclusion, 10 min of tSMS over a location within the sensori-motor network reduces functional connectivity within the same functional network.

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.

Lesion 3D modeling in transcranial MR-guided focused ultrasound thalamotomy.

Transcranial magnetic resonance-guided focused ultrasound (tMRgFUS) allows to perform incisionless thermoablation of deep brain structures. This feature makes it a very useful tool for the treatment of multiple neurological and psychiatric disorders. Currently, feedback of the thermoablation process is based on peak temperature readings assessed on real-time two-dimensional MRI thermometry. However, an accurate methodology relating thermal dosimetry with three-dimensional topography and temporal evolution of the lesion is still to be defined, thus hurdling the establishment of well-defined, evidence-based criteria to perform safe and effective treatments. In here we propose threshold-based thermoablation models to predict the volumetric topography of the lesion (whole lesion and necrotic core) in the short-to-mid-term based on thermal dosimetry estimated from intra-treatment MRI thermometry. To define and validate our models we retrospectively analyzed the data of sixty-three tMRgFUS thalamotomies for treating tremor. We used intra-treatment MRI thermometry to estimate whole-treatment three-dimensional thermal dose maps, defined either as peak temperature reached (Tmax) or thermal isoeffective dose (TID). Those maps were thresholded to find the dosimetric level that maximize the agreement (Sorensen-Dice coefficient - SDc) with the boundaries of the whole lesion and its core, assessed on T2w images 1-day (post-24h) and 3-months (post-3M) after treatment. Best predictions were achieved for the whole lesion at post-24h (SDc = 0.71), with Tmax /TID over 50.0 °C/90.5 CEM43. The core at post-24h and whole lesion at post-3M lesions reported a similar behavior in terms of shape accuracy (SDc ~0.35), and thermal dose thresholds ~55 °C/4100.0 CEM43. Finally, the optimal levels for post-3M core lesions were 55.5 °C/5800.0 CEM43 (SDc = 0.21). These thermoablation models could contribute to the real-time decision-making process and improve the outcome of tMRgFUS interventions both in terms of safety and efficacy.

Aberrant Salient and Corticolimbic Connectivity in Hypersexual Parkinson's Disease.

Introduction: Impulse control disorders (ICDs) represent a side effect of dopaminergic medication in Parkinson's disease (PD). Patients experience an excessive desire toward natural rewards paired with uncontrolled actions. Yet, the precise neural and behavioral mechanisms associated with ICDs and, importantly, each specific subdomain remain unclear. We aim to decipher resting-state and corticolimbic functional connectivity in PD patients with and without hypersexual ICD. Materials and Methods: Seventeen PD patients with hypersexuality (PD+HS) and 15 PD patients without hypersexuality (PD-HS) underwent two sessions (with and without medication) of resting-state functional magnetic resonance imaging and were compared with 17 healthy controls. Dual-regression independent component analyses extracted salience, sensorimotor, default-mode, and central executive networks. Seed-based functional connectivity with three striatal subdivisions (motor, associative, and limbic) was obtained and significant changes were correlated with key impulsivity and inhibitory measures. Results: Enhanced salience network (SN) activity represented by a significant rise in the right inferior frontal gyrus was found in PD+HS compared with PD-HS. Connectivity analyses revealed a functional disconnection between associative and limbic striatum with precuneus and superior parietal lobe in PD+HS, some connections explained by abnormal sexual behavior and inhibition in PD+HS. Conclusions: Hypersexual ICD is associated with enhanced SN signaling and corticolimbic disconnections, including striatal associative and limbic loops that contribute to altered control of sexually driven behavior and overall severity in PD and ICD. Impact statement We enlarge the neurobiological basis to one specific Parkinson's disease (PD) and impulse control disorder (ICD) (PD+ICD) subtype-that is, hypersexuality-and reveal its associated resting-state functional connectivity linked to altered behavior. We report enhanced salience network and right inferior frontal gyrus as part of the underlying resting-state functional networks in PD patients with hypersexuality (PD+HS). Corticolimbic changes were associated with sexual severity in PD+HS to hypoactive connectivity between associative-limbic striatum with precuneus and superior parietal lobe. The connectivity changes seen in PD+HS could explain baseline differences that engender aberrant control over sexual behavior in ICD.