Evidence from a rare case study for Hebbian-like changes in structural connectivity induced by long-term deep brain stimulation

BackgroundPatients with amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) show functional and structural connectivity alterations in the default mode network (DMN) while cerebrovascular disease (CeVD) shows functional and structural connectivity changes in the executive control network (ECN). Such disruptions are associated with memory and executive function impairment, respectively. Concurrent AD and CeVD pathology is associated with a higher rate of cognitive decline and differential neurodegenerative patterns. Together, such findings are likely reflective of different underlying pathology in AD with and without CeVD. However, few studies have examined the effect of CeVD on network functional connectivity (task-free functional magnetic resonance imaging (fMRI)) and structural connectivity (diffusion MRI) of the DMN and ECN in aMCI and AD using a hypothesis-driven multiple seed-based approach.MethodsWe examined functional and structural connectivity network changes in 39 aMCI, 50 aMCI+CeVD, 47 AD, 47 AD+CeVD, and 65 healthy controls (HCs) and their associations with cognitive impairment in the executive/attention and memory domains.ResultsWe demonstrate divergent DMN and ECN functional connectivity changes in CeVD and non-CeVD subjects. Compared with controls, intra-DMN hippocampal functional connectivity reductions were observed in both AD and AD+CeVD, while intra-DMN parietal and medial prefrontal-parietal functional connectivity was higher in AD+CeVD and aMCI+CeVD, but lower in AD. Intra-ECN frontal functional connectivity increases and fronto-parietal functional connectivity decreases occurred in CeVD but not non-CeVD subjects. Such functional connectivity alterations were related with cognitive impairment in a dissociative manner: intra-DMN functional connectivity changes were associated with worse cognition primarily in non-CeVD groups, while intra-ECN functional connectivity changes were associated with worse cognition primarily in CeVD groups. Additionally, CeVD and non-CeVD groups showed overlapping and distinct alterations in inter-network DMN-ECN functional connectivity depending on disease severity. In contrast to functional connectivity, CeVD groups had greater network structural connectivity damage compared with non-CeVD groups in both aMCI and AD patients. Network structural connectivity damage was associated with worse cognition.ConclusionsWe demonstrate differential functional and structural network changes between aMCI and AD patients with and without CeVD through diverging and deleterious network-based degeneration underlying domain-specific cognitive impairment.

The relationship between age-related changes in brain structural connectivity (SC) and functional connectivity (FC) with cognition is not well understood. Furthermore, it is not clear whether cognition is represented via a similar spatial pattern of FC and SC or instead is mapped by distinct sets of distributed connectivity patterns. To this end, we used a longitudinal, within-subject, multimodal approach aiming to combine brain data from diffusion-weighted MRI (DW-MRI), and functional MRI (fMRI) with behavioral evaluation, to better understand how changes in FC and SC correlate with changes in cognition in a sample of older adults. FC and SC measures were derived from the multimodal scans acquired at two time points. Change in FC and SC was correlated with 13 behavioral measures of cognitive function using Partial Least Squares Correlation (PLSC). Two of the measures indicate an age-related change in cognition and the rest indicate baseline cognitive performance. FC and SC—cognition correlations were expressed across several cognitive measures, and numerous structural and functional cortical connections, mainly cingulo-opercular, dorsolateral prefrontal, somatosensory and motor, and temporo-parieto-occipital, contributed both positively and negatively to the brain-behavior relationship. Whole-brain FC and SC captured distinct and independent connections related to the cognitive measures. Overall, we examined age-related function-structure associations of the brain in a comprehensive and integrated manner, using a multimodal approach. We pointed out the behavioral relevance of age-related changes in FC and SC. Taken together, our results highlight that the heterogeneity in distributed FC and SC connectivity patterns provide unique information about the variable nature of healthy cognitive aging.

Laser interstitial thermal therapy (LITT) is a minimally invasive surgery for mesial temporal lobe epilepsy (mTLE), but the effects of individual patient anatomy and location of ablation volumes affect seizure outcomes. The purpose of this study is to see if features of individual patient structural connectomes predict surgical outcomes after LITT for mTLE. This is a retrospective analysis of seizure outcomes of LITT for mTLE in 24 patients. We use preoperative diffusion tensor imaging (DTI) to simulate changes in structural connectivity after laser ablation. A two-step machine-learning algorithm is applied to predict seizure outcomes from the change in connectomic features after surgery. Although node-based network features such as clustering coefficient and betweenness centrality have some predictive value, changes in connection strength between mesial temporal regions predict seizure outcomes significantly better. Changes in connection strength between the entorhinal cortex (EC), and the insula, hippocampus, and amygdala, as well as between the temporal pole and hippocampus, predict Engel Class I outcomes with an accuracy of 88%. Analysis of the ablation location, as well as simulated, alternative ablations, reveals that a more medial, anterior, and inferior ablation volume is associated with a greater effect on these connections, and potentially on seizure outcomes. Our results indicate (1) that seizure outcomes can be retrospectively predicted with excellent accuracy using changes in structural connectivity, and (2) that favorable connectomic changes are associated with an ablation volume involving relatively mesial, anterior, and inferior locations. These results may provide a framework whereby individual pre-operative structural connectomes can be used to optimize ablation volumes and improve outcomes in LITT for mTLE.

Purpose The subthalamic nucleus (STN) and globus pallidus internus (GPi) targets for deep brain stimulation (DBS) can be defined by atlas coordinates or direct visualisation of the target on MRI. The aim of this study was to evaluate geometric differences between atlas-based targeting and MRI-guided direct targeting. Methods One-hundred-nine Parkinson’s disease or dystonia patients records who underwent DBS surgery between 2005 and 2016 were prospectively reviewed. MRI-guided direct targeting coordinates was used to implant 205 STN and 64 GPi electrodes and compared with atlas-based coordinates. Results The directly targeted coordinates (mean, SD, range) for STN were x: [9.9 ± 1.1 (7.1 − 13.2)], y: [−0.8 ± 1.1 (−4.2 − 2)] and z: [−4.7 ± 0.53 (−5.9 – −3.2)]. The mean value for the STN was 2.1 mm more medial (p < 0.0001), 1.2 mm more anterior (p < 0.0001) and 0.7 mm more ventral (p < 0.0001) than the atlas target. The targeted coordinates for GPi were x: [22.3 ± 2.0 (17.8 − 26.1)], y: [−0.2 ± 2.2 (−4.5 − 3.4)], z: [−4.3 ± 0.8 (−6.2 – −2.3)]. The mean value for the GPi was 2.2 mm (p < 0.001) more posterior and 0.3 mm (p < 0.01) more ventral than the atlas-based coordinates. Conclusion MRI-guided targeting may be more accurate than atlas-based targeting due to individual variations in anatomy.

IntroductionThe globus pallidus internus (GPi) region has evolved as a potential target for deep brain stimulation (DBS) in Parkinson’s disease (PD). DBS of the GPi (GPi DBS) is an established, safe and effective method for addressing many of the motor symptoms associated with advanced PD. It is important that clinicians fully understand this target when considering GPi DBS for individual patients.MethodsThe literature on GPi DBS in PD has been comprehensively reviewed, including the anatomy, physiology and potential pitfalls that may be encountered during surgical targeting and post-operative management. Here, we review and address the implications of lead location on GPi DBS outcomes. Additionally, we provide a summary of randomized controlled clinical trials conducted on DBS in PD, together with expert commentary on potential applications of the GPi as target. Finally, we highlight future technologies that will likely impact GPi DBS, including closed-loop adaptive approaches (e.g. sensing-stimulating capabilities), advanced methods for image-based targeting and advances in DBS programming, including directional leads and pulse shaping.ResultsThere are important disease characteristics and factors to consider prior to selecting the GPi as the DBS target of PD surgery. Prior to and during implantation of the leads it is critical to consider the neuroanatomy, which can be defined through the combination of image-based targeting and intraoperative microelectrode recording strategies. There is an increasing body of literature on GPi DBS in patients with PD suggesting both short- and long-term benefits. Understanding the GPi target can be useful in choosing between the subthalamic (STN), GPi and ventralis intermedius nucleus as lead locations to address the motor symptoms and complications of PD.ConclusionGPi DBS can be effectively used in select cases of PD. As the ongoing DBS target debate continues (GPi vs. STN as DBS target), clinicians should keep in mind that GPi DBS has been shown to be an effective treatment strategy for a variety of symptoms, including bradykinesia, rigidity and tremor control. GPi DBS also has an important, direct anti-dyskinetic effect. GPi DBS is easier to program in the outpatient setting and will allow for more flexibility in medication adjustments (e.g. levodopa). Emerging technologies, including GPi closed-loop systems, advanced tractography-based targeting and enhanced programming strategies, will likely be future areas of GPi DBS expansion. We conclude that although the GPi as DBS target may not be appropriate for all PD patients, it has specific clinical advantages.Electronic supplementary materialThe online version of this article (10.1007/s40120-020-00220-5) contains supplementary material, which is available to authorized users.

Response inhibition, the cancellation of planned movement, is essential for everyday motor control. Extensive fMRI and brain stimulation research provides evidence for the crucial role of a number of cortical and subcortical regions in response inhibition, including the subthalamic nucleus (STN), pre-supplementary motor area (preSMA), and the inferior frontal gyrus (IFG). Current models assume that these regions operate as a network, with action cancellation originating in the cortical areas and then executed rapidly via the subcortex. Response inhibition slows in older age, a change that has been attributed to deterioration or changes in the connectivity and integrity of this network. However, previous research has mainly used whole-brain approaches when investigating changes in structural connectivity across the lifespan, or have used simpler measures to investigate structural ageing. Here, we used high-resolution quantitative and diffusion MRI to extensively examine the anatomical changes that occur in this network across the lifespan. We found substantial changes in iron concentration in these tracts, increases in the apparent diffusion coefficient, and some evidence for demyelination. Conversely, we found very little evidence for age-related anatomical changes in the regions themselves. We propose that some of the functional changes observed in these regions in older adult populations (e.g., increased BOLD recruitment) are a reflection of alterations to the connectivity between the regions, rather than localised regional change.

The objective of this study was to evaluate clinical features and response to deep brain stimulation (DBS) in G2019S LRRK2-Parkinson disease (LRRK2-PD) and idiopathic PD (IPD). The authors conducted a clinic-based cohort study of PD patients recruited from the Mount Sinai Beth Israel Genetics database of PD studies. The cohort included 87 participants with LRRK2-PD (13 who underwent DBS) and 14 DBS participants with IPD enrolled between 2009 and 2017. The baseline clinical features, including motor ratings and levodopa-equivalent daily dose (LEDD), were compared among LRRK2-PD patients with and without DBS, between LRRK2-PD with DBS and IPD with DBS, and between LRRK2-PD with subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) DBS. Longitudinal motor scores (Unified Parkinson's Disease Rating Scale-part III) and medication usage were also assessed pre- and postoperatively. Compared to LRRK2-PD without DBS (n = 74), the LRRK2-PD with DBS cohort (n = 13) had a significantly younger age of onset, longer disease duration, were more likely to have dyskinesia, and were less likely to experience hand tremor at disease onset. LRRK2-PD participants were also more likely to be referred for surgery because of severe dyskinesia (11/13 [85%] vs 6/14 [43%], p = 0.04) and were less likely to be referred for medically refractory tremor (0/13 [0%] vs 6/14 [43%], p = 0.02) than were IPD patients. Among LRRK2-PD patients, both STN-DBS and GPi-DBS targets were effective, although the sample size was small for both groups. There were no revisions or adverse effects reported in the GPi-DBS group, while 2 of the LRRK2-PD participants who underwent STN-DBS required revisions and a third reported depression as a stimulation-related side effect. Medication reduction favored the STN group. The LRRK2-PD cohort referred for DBS had a slightly different profile, including earlier age of onset and dyskinesia. Both the STN and GPi DBS targets were effective in symptom suppression. Patients with G2019S LRRK2 PD were well-suited for DBS therapy and had favorable motor outcomes regardless of the DBS target. LRRK2-DBS patients had longer disease durations and tended to have more dyskinesia. Dyskinesia commonly served as the trigger for DBS surgical candidacy. Medication-refractory tremor was not a common indication for surgery in the LRRK2 cohort.

The benefit of deep brain stimulation (DBS) for Parkinson disease (PD) may depend on connectivity between the stimulation site and other brain regions, but which regions and whether connectivity can predict outcome in patients remain unknown. Here, we identify the structural and functional connectivity profile of effective DBS to the subthalamic nucleus (STN) and test its ability to predict outcome in an independent cohort. A training dataset of 51 PD patients with STN DBS was combined with publicly available human connectome data (diffusion tractography and resting state functional connectivity) to identify connections reliably associated with clinical improvement (motor score of the Unified Parkinson Disease Rating Scale [UPDRS]). This connectivity profile was then used to predict outcome in an independent cohort of 44 patients from a different center. In the training dataset, connectivity between the DBS electrode and a distributed network of brain regions correlated with clinical response including structural connectivity to supplementary motor area and functional anticorrelation to primary motor cortex (p < 0.001). This same connectivity profile predicted response in an independent patient cohort (p < 0.01). Structural and functional connectivity were independent predictors of clinical improvement (p < 0.001) and estimated response in individual patients with an average error of 15% UPDRS improvement. Results were similar using connectome data from normal subjects or a connectome age, sex, and disease matched to our DBS patients. Effective STN DBS for PD is associated with a specific connectivity profile that can predict clinical outcome across independent cohorts. This prediction does not require specialized imaging in PD patients themselves. Ann Neurol 2017;82:67-78.

Functional connectivity-based compensation in the brains of non-demented older adults and the influence of lifestyle: A longitudinal 7-year study.

Response inhibition, the cancellation of planned movement, is essential for everyday motor control. Extensive fMRI and brain stimulation research provides evidence for the crucial role of a number of cortical and subcortical regions in response inhibition, including the subthalamic nucleus (STN), presupplementary motor area (preSMA) and the inferior frontal gyrus (IFG). Current models assume that these regions operate as a network, with action cancellation originating in the cortical areas and then executed rapidly via the subcortex. Response inhibition slows in older age, a change that has been attributed to deterioration or changes in the connectivity and integrity of this network. However, previous research has mainly used whole-brain approaches when investigating changes in structural connectivity across the lifespan or has used simpler measures to investigate structural ageing. Here, we used high-resolution quantitative and diffusion MRI to extensively examine the anatomical changes that occur in this network across the lifespan. We found age-related changes in iron concentration in these tracts, increases in the apparent diffusion coefficient and some evidence for a decrease in myelin content. Conversely, we found very little evidence for age-related anatomical changes in the regions themselves. We propose that some of the functional changes observed in these regions in older adult populations (e.g., increased BOLD recruitment) are a reflection of alterations to the connectivity between the regions rather than localised regional change.

Background/Introduction: Parkinson’s disease (PD) is a progressive neurodegenerative disorder treated with deep brain stimulation (DBS) for advanced stages, targeting the subthalamic nucleus (STN) or the internal globus pallidus (GPi). Despite DBS’s symptomatic benefits, cerebrovascular events (CVEs) remain a concern. This study assessed CVE risk in PD patients undergoing DBS. Methods: We performed a systematic review and meta-analysis following PRISMA 2020 guidelines. Studies published between 2014 and 2024 that reported CVEs in PD patients treated with DBS-STN or DBS-GPi were included. Data on CVEs, DBS targets, perioperative period, and microelectrode recording (MER) use were extracted, and probability proportions were pooled using a random-effects model. Results: Twenty-three studies (4795 patients) were included. The overall CVE probability was 2.71% (95% CI: 2.27–3.18%). Descriptive probabilities were 2.56% (95% CI: 1.94–3.24%) for STN and 0.93% (95% CI: 0.00–3.08%) for GPi. Hemorrhagic events were most common (STN: 2.47%; GPi: 1.98%), while ischemic events were rare (STN: 0.07%; GPi: 1.98%). Note that GPi estimates are based on a considerably smaller population and should be interpreted with caution. Postoperative CVEs (1.74%) were more frequent than intraoperative events (0.17%), and MER use did not significantly alter risk (MER: 2.89% vs. NON-MER: 2.92%). Conclusions: Our results suggest that DBS in PD is associated with a relatively low CVE risk (~2.7%), with hemorrhage being the most frequent type; CVEs remain a potential risk factor. Comprehensive evaluation of patient-specific factors and further prospective studies focusing on CVE outcomes are essential to optimize DBS safety in managing PD.

Deep brain stimulation (DBS) has emerged as a safe, effective, and reversible treatment for a number of movement disorders. This has prompted investigation of its use for other applications including psychiatric disorders. In recent years, DBS has been introduced for the treatment of obsessive compulsive disorder (OCD), which is characterized by recurrent unwanted thoughts or ideas (obsessions) and repetitive behaviors or mental acts performed in order to relieve these obsessions (compulsions). Abnormal activity in cortico-striato-thalamo-cortical (CSTC) circuits including the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), ventral striatum, and mediodorsal (MD) thalamus has been implicated in OCD. To this end a number of DBS targets including the anterior limb of the internal capsule (ALIC), ventral capsule/ventral striatum (VC/VS), ventral caudate nucleus, subthalamic nucleus (STN), and nucleus accumbens (NAc) have been investigated for the treatment of OCD. Despite its efficacy and widespread use in movement disorders, the mechanism of DBS is not fully understood, especially as it relates to psychiatric disorders. While initially thought to create a functional lesion akin to ablative procedures, it is increasingly clear that DBS may induce clinical benefit through activation of axonal fibers spanning the CSTC circuits, alteration of oscillatory activity within this network, and/or release of critical neurotransmitters. In this article we review how the use of DBS for OCD informs our understanding of both the mechanisms of DBS and the circuitry of OCD. We review the literature on DBS for OCD and discuss potential mechanisms of action at the neuronal level as well as the broader circuit level.

BackgroundNotwithstanding the large improvement in motor function in Parkinson’s disease (PD) patients treated with deep brain stimulation (DBS), apathy may increase. Postoperative apathy cannot always be related to a dose reduction of dopaminergic medication and stimulation itself may play a role. ObjectiveWe studied whether apathy in DBS-treated PD patients could be a stimulation effect. MethodsIn 26 PD patients we acquired apathy scores before and >6 months after DBS of the subthalamic nucleus (STN). Magnetoencephalography recordings (ON and OFF stimulation) were performed ≥6 months after DBS placement. Change in apathy severity was correlated with (i) improvement in motor function and dose reduction of dopaminergic medication, (ii) stimulation location (merged MRI and CT-scans) and (iii) stimulation-related changes in functional connectivity of brain regions that have an alleged role in apathy. ResultsAverage apathy severity significantly increased after DBS (p < 0.001) and the number of patients considered apathetic increased from two to nine. Change in apathy severity did not correlate with improvement in motor function or dose reduction of dopaminergic medication. For the left hemisphere, increase in apathy was associated with a more dorsolateral stimulation location (p = 0.010). The increase in apathy severity correlated with a decrease in alpha1 functional connectivity of the dorsolateral prefrontal cortex (p = 0.006), but not with changes of the medial orbitofrontal or the anterior cingulate cortex. ConclusionsThe present observations suggest that apathy after STN-DBS is not necessarily related to dose reductions of dopaminergic medication, but may be an effect of the stimulation itself. This highlights the importance of determining optimal DBS settings based on both motor and non-motor symptoms.

BackgroundPrevious studies reported reduced volumes of many brain regions for temporal lobe epilepsy (TLE). It has also been suggested that there may be widespread changes in network features of TLE patients. It is not fully understood, however, how these two observations are related.MethodsUsing magnetic resonance imaging data, we perform parcellation of the brains of 22 patients with left TLE and 39 non-epileptic controls. In each parcellated region of interest (ROI) we computed the surface area and, using diffusion tensor imaging and deterministic tractography, infer the number of streamlines and their average length between each pair of connected ROIs. For comparison to previous studies, we use a connectivity ‘weight’ and investigate how ROI surface area, number of streamlines & mean streamline length contribute to such weight.ResultsWe find that although there are widespread significant changes in surface area and position of ROIs in patients compared to controls, the changes in connectivity are much more subtle. Significant changes in connectivity weight can be accounted for by decreased surface area and increased streamline count.ConclusionChanges in the surface area of ROIs can be a reliable biomarker for TLE with a large influence on connectivity. However, changes in structural connectivity via white matter streamlines are more subtle with a relatively lower influence on connection weights.

Deep brain stimulation for obsessive compulsive disorder: A literature review