Mammillothalamic Tract Research Articles

Neurophysiologic Characteristics of the Anterior Nucleus of the Thalamus during Deep Brain Stimulation Surgery for Epilepsy

Introduction: Anterior nucleus of the thalamus (ANT) deep brain stimulation (DBS) is an increasingly promising treatment option for refractory epilepsy. Optimal therapeutic benefit has been associated with stimulation at the junction of ANT and the mammillothalamic tract (mtt), but electrophysiologic markers of this target are lacking. The present study examined microelectrode recordings (MER) during DBS to identify unique electrophysiologic characteristics of ANT and the ANT-mtt junction. Methods: Ten patients with medically refractory epilepsy underwent MER during ANT-DBS implantation under general anesthesia. MER locations were determined based on coregistration of preoperative MRI, postoperative CT, and a stereotactic atlas of the thalamus (Morel atlas). Several neurophysiological parameters including single unit spiking rate, bursting properties, theta and alpha power and cerebrospinal fluid (CSF)-normalized root mean square (NRMS) of multiunit activity were characterized at recording depths and compared to anatomic boundaries. Results: From sixteen hemispheres, 485 recordings locations were collected from a mean of 30.3 (15.64 ± 5.0 mm) recording spans. Three-hundred and ninety-four of these recording locations were utilized further for analysis of spiking and bursting rates, after excluding recordings that were more than 8 mm above the putative ventral ANT border. The ANT region exhibited discernible features including: (1) mean spiking rate (7.52 Hz ± 6.9 Hz; one-way analysis of variance test, p = 0.014 when compared to mediodorsal nucleus of the thalamus [MD], mtt, and CSF), (2) the presence of bursting activity with 40% of ANT locations (N = 59) exhibited bursting versus 24% the mtt (χ2; p < 0.001), and 32% in the MD (p = 0.38), (3) CSF-NRMS, a proxy for neuronal density, exhibited well demarcated changes near the entry and exit of ANT (linear regression, R = −0.33, p < 0.001). Finally, in the ANT, both theta (4–8 Hz) and alpha band power (9–12 Hz) were negatively correlated with distance to the ventral ANT border (linear regression, p < 0.001 for both). The proportion of recordings with spiking and bursting activity was consistently highest 0–2 mm above the ventral ANT border with the mtt. Conclusion: We observed several electrophysiological markers demarcating the ANT superior and inferior borders including multiple single cell and local field potential features. A local maximum in neural activity just above the ANT-mtt junction was consistent with the previously described optimal target for seizure reduction. These features may be useful for successful targeting of ANT-DBS for epilepsy.

High angular resolution diffusion-weighted imaging and higher order tractography of the white matter tracts in the anterior thalamic area: Insights into deep brain stimulation targeting

BackgroundDeep brain stimulation of the anterior nucleus of the thalamus (ANT) is emerging EU/US-approved form of therapy for drug-resistant focal epilepsy. Its mechanism of action is not yet fully understood, and the patient outcomes in epilepsy appear less consistent compared to for instance movement disorders. Furthermore, very little anatomy-based information, such as tractography of relevant fiber systems, exists guiding DBS therapy at present. ObjectiveTo demonstrate ANT-related fiber systems based on histology in vivo employing multi-shell/multi-tissue constrained spherical deconvolution (MSMT-CSD) based deterministic and probabilistic tractography using a sophisticated scanning protocol of 3T high angular resolution diffusion-weighted imaging (HARDI) data in healthy volunteers. MethodHARDI data was acquired from five healthy volunteers in a 3T Siemens MAGNETOM Skyra Magnetic resonance imaging (MRI) machine using multiple b-values (1000, 2000, and 3000), 64 directions, and further preprocessed for tractography. MSMT-CSD-based deterministic and probabilistic tractography was performed from selected fiber systems based on existing literature. ResultsMultiple fiber systems were identified: The anterior thalamic radiation (ANT), the thalamo-cingulate tract, the inferior thalamic peduncle (with remote termination areas in the amygdala, the ventral tegmental area, and the occipital cortex), and the mammillothalamic tract. In addition, we observed three parallel connections to the hippocampus (via the cingulum bundle, the fornix, and the temporo-pulvinar pathway). Interestingly, different seed areas in ANT complex mimicking DBS contact locations resulted in visualization of different fiber systems. DiscussionThe connections of the ANT are complex and different stimulation sites are likely to affect different networks depending on lead locations and the selection of the active contact. ConclusionsIn-depth understanding of the network of anatomical structures related to the ANT is likely to influence therapy outcomes. A hypothetical model of neuronal networks affected by different DBS lead contact locations is proposed. A more profound understanding of neuroanatomic characteristics may guide stereotactic implantation and subsequent programming to optimize outcomes.

Arterial spin labeling perfusion in acute Wernicke encephalopathy: a case series discussion

Wernicke’s encephalopathy (WE) is a life-threatening neurologic disorder resulting from thiamine (vitamin B1) deficiency that can be secondary to chronic alcohol abuse, gastrointestinal surgery, systemic infectious and non-infectious diseases, and chemotherapy. WE is classically characterized on MRI by reduced diffusion and T2 prolongation along the mammillothalamic tracts, periaqueductal gray and tectal plate. We present two patients with acute WE who had baseline arterial spin labeling (ASL) perfusion at the time of presentation, demonstrating increase in cerebral blood flow (CBF) within the classically involved brain regions and concurrent global cerebral cortical hypoperfusion. Both patients were successfully treated with intravenous thiamine infusion. Post-treatment MRI demonstrated improvement of reduced diffusion and normalization of CBF within the involved structures. Prior histopathological studies have documented prominent undulation and luminal dilatation of arteries and arterioles in acute WE lesions, likely explaining the increased perfusion shown by imaging. The root of this pathophysiologic process may trace back to thiamine’s biochemical role in maintaining osmotic gradients and glucose metabolism, that if failed can lead to arterial hyper-perfusion. Our findings show that ASL-CBF can highlight the underlying pathophysiology in patients with acute WE by demonstrating increased CBF in involved central structures. This luxury perfusion may be a compensatory or protective mechanism by which increased metabolic demand is met in the acute setting and which, if treated timely, will show normalization of CBF on ASL imaging.

E.5 Large scale network changes immediately after Magnetic Resonance Imaging-Guided Laser Interstitial Thermal Therapy (MRgLITT) for hypothalamic hamartoma

Background: Hypothalamic hamartomas (HH) are a challenging cause of seizure in children, partly because the neural circuitry involved in ictogenesis is incompletely understood. We review our institutions’ use of magnetic resonance imaging-guided laser interstitial thermal therapy (MRgLITT) to treat hypothalamic hamartoma (HH) with resting-state fMRI performed immediately before and after ablation. Methods: Seed-based whole brain connectivity to thalamic regions of interest was performed immediately pre- and post- MRgLITT. Multivariable generalized linear models were used to correlate resting-state data with seizure outcomes. Results: Eight patients underwent MRgLITT treatments for HH, with a mean follow up of 29 months. Four patients (50%) were seizure free at 12 months and two (25%) had a significant improvement in seizure frequency. We identified reduced thalamocortical connectivity involving the anterior cingulate and posterior parietal regions, consistent with disconnection of the mammillothalamic tract and interruption of Papez circuit. Large-scale thalamocortical connectivity changes were driven by children who subsequently became seizure free. Conclusions: Disconnection of the mammillothalamic tract and interruption of thalamic circuitry in patients undergoing MRgLITT for HH appears to be associated with improved seizure outcomes. The ability to assess network changes immediately post- MRgLITT could enable operative adjustments to be made mid-procedure to optimize seizure outcome in real time.

Korsakoff's Syndrome and Alzheimer's Disease-Commonalities and Specificities of Volumetric Brain Alterations within Papez Circuit.

Background: Alzheimer's disease (AD) and Korsakoff's syndrome (KS) are two major neurocognitive disorders characterized by amnesia but AD is degenerative while KS is not. The objective is to compare regional volume deficits within the Papez circuit in AD and KS, considering AD progression. Methods: 18 KS patients, 40 AD patients (20 with Moderate AD (MAD) matched on global cognitive deficits with KS patients and 20 with Severe AD (SAD)), and 70 healthy controls underwent structural MRI. Volumes of the hippocampi, thalami, cingulate gyri, mammillary bodies (MB) and mammillothalamic tracts (MTT) were extracted. Results: For the cingulate gyri, and anterior thalamic nuclei, all patient groups were affected compared to controls but did not differ between each other. Smaller volumes were observed in all patient groups compared to controls in the mediodorsal thalamic nuclei and MB, but these regions were more severely damaged in KS than AD. MTT volumes were damaged in KS only. Hippocampi were affected in all patient groups but more severely in the SAD than in the KS and MAD. Conclusions: There are commonalities in the pattern of volume deficits in KS and AD within the Papez circuit with the anterior thalamic nuclei, cingulate cortex and hippocampus (in MAD only) being damaged to the same extent. The specificity of KS relies on the alteration of the MTT and the severity of the MB shrinkage. Further comparative studies including other imaging modalities and a neuropsychological assessment are required.

Is Thalamic DBS Synergistic With VNS in Drug Resistant Genetic Generalized Epilepsy? (P5-1.001)

<h3>Objective:</h3> To report prolonged seizure freedom and improved quality of life after combining anterior nucleus of the thalamus deep brain stimulation (ANT-DBS) with vagus nerve stimulation (VNS) in a patient with drug resistant genetic generalized epilepsy (GGE). <h3>Background:</h3> Neuromodulation remains at forefront of management in patients with drug-resistant epilepsies though efficacy has been palliative and FDA approved in focal epilepsies. While polytherapy with anti-seizure medications (ASMs) is common, dual neuromodulation has received limited attention. <h3>Design/Methods:</h3> A 32-year-old female patient with drug resistant GGE who failed 10 antiseizure medications underwent video-EEG monitoring. EEG revealed 3–3.5 Hz generalized polyspike-and-wave discharges and generalized paroxysmal fast activity in brief run lasting less than 3 seconds increased during sleep. Seizures were not recorded. VNS model 106 Aspire SR was implanted at age 23 achieving parameters of 1.5 mA, 25 Hz, 250 μs, 14 sec on, 1.1 min off. Despite improvement with seizure reduction, ongoing monthly convulsions resulted in recurrent injuries. The patient subsequently underwent bilateral ANT-DBS placement with inferior most contacts on both sides well-positioned at the junction of the mammillothalamic tracts for monopolar stimulation at 5 V, 145 Hz, and 90 μs. <h3>Results:</h3> Neuro- “modulation” was observed in our patient with VNS following implantation of ANT-DBS by gradual reduction diminishing seizure frequency, intensity, and duration to ultimately become seizure-free for 21 months. Stable doses of Onfi 20 mg po bid and Keppra 1500 mg po bid were continued. After combining ANT-DBS with her incomplete VNS response she married, became employed, and was able to retain driving privileges and lead an independent lifestyle. <h3>Conclusions:</h3> Identifying a subset of patients with GGE responsive to polyneuromodulation promises personalized therapy for those with life-altering effects from generalized seizures. We speculate that the thalamic network connectivity may be modulated by dual ANT-DBS and VNS, leading to targeted neurobiological therapy in some patients with GGE. <b>Disclosure:</b> Dr. Khan has nothing to disclose. Erik Middlebrooks has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Varian Medical Systems Inc. Erik Middlebrooks has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Boston Scientific Corp. The institution of Erik Middlebrooks has received research support from Varian Medical Systems Inc. Dr. Freund has nothing to disclose. Sanjeet S. Grewal, MD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medtronic. Dr. Tatum has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Bioserenity. Dr. Tatum has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Dr. Tatum has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Defense Law Firm on behalf of a patient with epilepsy with funds donated to the Epilepsy Foundation of America. The institution of Dr. Tatum has received research support from Esai. The institution of Dr. Tatum has received research support from Mayo Clinic. The institution of Dr. Tatum has received research support from Liva Nova. The institution of Dr. Tatum has received research support from Engage Pharmaceuticals. The institution of Dr. Tatum has received research support from Xenon. Dr. Tatum has received publishing royalties from a publication relating to health care. Dr. Tatum has received publishing royalties from a publication relating to health care.

Teaching NeuroImages: Persistent anterograde amnesia due to sequential, bilateral vascular damage to the Papez circuit

A 62-year-old previously cognitively intact man presented to the emergency department with acute impairment of anterograde memory (ability to form new memories).1 Head CT did not show acute changes; however, amnesia persisted. MRI disclosed an acute infarct in the left posterior hippocampus and a nonacute lacunar stroke in the right anterior thalamus (figure). Memory testing showed severe deficits in verbal and visual memory, persisting after 2 months. Bilateral lesions located anywhere in the Papez circuit (hippocampal formations, mammillary bodies, anterior thalamic nuclei, cingulate and parahippocampal cortices, and their connections via fornix and mammillothalamic tracts) may be implicated in marked, persistent anterograde memory deficits.1,2 The hippocampus receives its blood supply from collateral branches of the posterior cerebral artery and the anterior choroidal artery.3 The anterior thalamus is supplied by the tuberothalamic artery.4

Mammillary body abnormalities and cognitive outcomes in children cooled for neonatal encephalopathy.

To evaluate mammillary body abnormalities in school-age children without cerebral palsy treated with therapeutic hypothermia for neonatal hypoxic-ischaemic encephalopathy (cases) and matched controls, and associations with cognitive outcome, hippocampal volume, and diffusivity in the mammillothalamic tract (MTT) and fornix. Mammillary body abnormalities were scored from T1-weighted magnetic resonance imaging (MRI) in 32 cases and 35 controls (median age [interquartile range] 7 years [6 years 7 months-7 years 7 months] and 7 years 4 months [6 years 7 months-7 years 7 months] respectively). Cognition was assessed using the Wechsler Intelligence Scale for Children, Fourth Edition. Hippocampal volume (normalized by total brain volume) was measured from T1-weighted MRI. Radial diffusivity and fractional anisotropy were measured in the MTT and fornix, from diffusion-weighted MRI using deterministic tractography. More cases than controls had mammillary body abnormalities (34% vs 0%; p< 0.001). Cases with abnormal mammillary bodies had lower processing speed (p= 0.016) and full-scale IQ (p= 0.028) than cases without abnormal mammillary bodies, and lower scores than controls in all cognitive domains (p< 0.05). Cases with abnormal mammillary bodies had smaller hippocampi (left p= 0.016; right p= 0.004) and increased radial diffusivity in the right MTT (p= 0.004) compared with cases without mammillary body abnormalities. Cooled children with mammillary body abnormalities at school-age have reduced cognitive scores, smaller hippocampi, and altered MTT microstructure compared with those without mammillary body abnormalities, and matched controls. Cooled children are at higher risk of mammillary body abnormalities than controls. Abnormal mammillary bodies are associated with reduced cognitive scores and smaller hippocampi. Abnormal mammillary bodies are associated with altered mammillothalamic tract diffusivity.

In vivo probabilistic atlas of white matter tracts of the human subthalamic area combining track density imaging and optimized diffusion tractography

The human subthalamic area is a region of high anatomical complexity, tightly packed with tiny fiber bundles. Some of them, including the pallidothalamic, cerebello-thalamic, and mammillothalamic tracts, are relevant targets in functional neurosurgery for various brain diseases. Diffusion-weighted imaging-based tractography has been suggested as a useful tool to map white matter pathways in the human brain in vivo and non-invasively, though the reconstruction of these specific fiber bundles is challenging due to their small dimensions and complex anatomy. To the best of our knowledge, a population-based, in vivo probabilistic atlas of subthalamic white matter tracts is still missing. In the present work, we devised an optimized tractography protocol for reproducible reconstruction of the tracts of subthalamic area in a large data sample from the Human Connectome Project repository. First, we leveraged the super-resolution properties and high anatomical detail provided by short tracks track-density imaging (stTDI) to identify the white matter bundles of the subthalamic area on a group-level template. Tracts identification on the stTDI template was also aided by visualization of histological sections of human specimens. Then, we employed this anatomical information to drive tractography at the subject-level, optimizing tracking parameters to maximize between-subject and within-subject similarities as well as anatomical accuracy. Finally, we gathered subject level tracts reconstructed with optimized tractography into a large-scale, normative population atlas. We suggest that this atlas could be useful in both clinical anatomy and functional neurosurgery settings, to improve our understanding of the complex morphology of this important brain region.

Deep brain stimulation of the anterior nucleus of the thalamus for drug‐resistant epilepsy: Long‐term efficacy and outcomes from a prospective cohort

AbstractAimThe anterior nucleus of the thalamus (ANT) has been one of the deep brain stimulation (DBS) targets for drug‐resistant epilepsy. This study aims to investigate the control of seizures among patients with ANT DBS for epilepsy. We have pioneered DBS for epilepsy in Hong Kong since 2015 and this study aims to report the long‐term outcomes from a prospective cohort.MethodsThis is a prospective cohort study of ANT DBS for adult patients with drug‐resistant epilepsy, who are unsuitable for resective epilepsy surgery.ResultsSix patients (3 females and 3 males, mean age 31.3) received bilateral ANT DBS in a tertiary university hospital from 2015 to 2018 (one in 2015, two in 2017 and three in 2018). Both frontal transventricular and parietal approaches were used. The active contacts were selected based on the closest Euclidean distance to the mammillothalamic tract and ANT junction. Five of the six cases (83.3%) achieved greater than 50% reduction in seizures after the operations. The median percentage of reduction in seizures was 58.5% at 3 years after DBS (range, 32.7%–80%). Overall, there was a trend of improving seizure control rate from year 1 to year 6 after the ANT DBS operations.ConclusionsThis is the first report of ANT DBS for drug‐resistant epilepsy in Hong Kong. The results are encouraging. ANT DBS for drug‐resistant epilepsy is effective and sustained in long term. The treatment option of ANT DBS should be considered in suitable candidates with drug‐resistant epilepsy in our locality.

Korsakoff Syndrome: A Chronic Nutritional Deficiency Neuropsychiatric condition

In this review we have focused on Korsakoff syndrome, which is an aftermath of Wernicke encephalopathy (WE). Wernicke-Encephalopathy is neuropathologically marked by thiamine or vitamin B1 deficiency, typically induced by excessive alcohol use over an extended period of time in alcoholic patients, while in Nonalcoholic patients, it may be due to impaired utilization or accelerated usage of thiamine. Wernicke-Korsakoff syndrome (WKS) affects the brain region such as the mammillary bodies, periaqueductal and periventricular grey matter, colliculi bodies, and thalamus. The classic triads of WE are ophthalmoplegia, Nystagmus, and ataxia. The brain is examined using MRI and shows damage to the nuclei or memory transit- papez circuit that connects mamillary bodies to the anterior thalamus using the mammillothalamic tract responsible for the recollective memory in the diencephalon. Patients can be treated by parenteral thiamine administration and by abstinence of alcohol within their lifestyle. Keywords: Korsakoff Syndrome, alcoholic, non-alcoholic, Alzheimer's, memory-loss Wernicke encephalopathy, Wernicke-Korsakoff syndrome

Identifying the neural network for neuromodulation in epilepsy through connectomics and graphs.

Deep brain stimulation is a treatment option for patients with drug-resistant epilepsy. The precise mechanism of neuromodulation in epilepsy is unknown, and biomarkers are needed for optimizing treatment. The aim of this study was to describe the neural network associated with deep brain stimulation targets for epilepsy and to explore its potential application as a novel biomarker for neuromodulation. Using seed-to-voxel functional connectivity maps, weighted by seizure outcomes, brain areas associated with stimulation were identified in normative resting state functional scans of 1000 individuals. To pinpoint specific regions in the normative epilepsy deep brain stimulation network, we examined overlapping areas of functional connectivity between the anterior thalamic nucleus, centromedian thalamic nucleus, hippocampus and less studied epilepsy deep brain stimulation targets. Graph network analysis was used to describe the relationship between regions in the identified network. Furthermore, we examined the associations of the epilepsy deep brain stimulation network with disease pathophysiology, canonical resting state networks and findings from a systematic review of resting state functional MRI studies in epilepsy deep brain stimulation patients. Cortical nodes identified in the normative epilepsy deep brain stimulation network were in the anterior and posterior cingulate, medial frontal and sensorimotor cortices, frontal operculum and bilateral insulae. Subcortical nodes of the network were in the basal ganglia, mesencephalon, basal forebrain and cerebellum. Anterior thalamic nucleus was identified as a central hub in the network with the highest betweenness and closeness values, while centromedian thalamic nucleus and hippocampus showed average centrality values. The caudate nucleus and mammillothalamic tract also displayed high centrality values. The anterior cingulate cortex was identified as an important cortical hub associated with the effect of deep brain stimulation in epilepsy. The neural network of deep brain stimulation targets shared hubs with known epileptic networks and brain regions involved in seizure propagation and generalization. Two cortical clusters identified in the epilepsy deep brain stimulation network included regions corresponding to resting state networks, mainly the default mode and salience networks. Our results were concordant with findings from a systematic review of resting state functional MRI studies in patients with deep brain stimulation for epilepsy. Our findings suggest that the various epilepsy deep brain stimulation targets share a common cortico-subcortical network, which might in part underpin the antiseizure effects of stimulation. Interindividual differences in this network functional connectivity could potentially be used as biomarkers in selection of patients, stimulation parameters and neuromodulation targets.

Compromised mammillary body connectivity and psychotic symptoms in mice with di- and mesencephalic ablation of ST8SIA2

Altered long-range connectivity is a common finding across neurodevelopmental psychiatric disorders, but causes and consequences are not well understood. Genetic variation in ST8SIA2 has been associated with schizophrenia, autism, and bipolar disorder, and St8sia2−/− mice show a number of related neurodevelopmental and behavioral phenotypes. In the present study, we use conditional knockout (cKO) to dissect neurodevelopmental defects and behavioral consequences of St8sia2 deficiency in cortical interneurons, their cortical environment, or in the di- and mesencephalon. Neither separate nor combined cortical and diencephalic ablation of St8sia2 caused the disturbed thalamus-cortex connectivity observed in St8sia2−/− mice. However, cortical ablation reproduced hypoplasia of corpus callosum and fornix and mice with di- and mesencephalic ablation displayed smaller mammillary bodies with a prominent loss of parvalbumin-positive projection neurons and size reductions of the mammillothalamic tract. In addition, the mammillotegmental tract and the mammillary peduncle, forming the reciprocal connections between mammillary bodies and Gudden’s tegmental nuclei, as well as the size of Gudden’s ventral tegmental nucleus were affected. Only mice with these mammillary deficits displayed enhanced MK-801-induced locomotor activity, exacerbated impairment of prepulse inhibition in response to apomorphine, and hypoanxiety in the elevated plus maze. We therefore propose that compromised mammillary body connectivity, independent from hippocampal input, leads to these psychotic-like responses of St8sia2-deficient mice.

Anterior Nucleus of Thalamus Deep Brain Stimulation: A Clinical-Based Analysis of the Ideal Target in Drug-Resistant Epilepsy

Introduction: Deep brain stimulation of the anterior nucleus of thalamus (ANT-DBS) is an approved procedure for drug-resistant epilepsy. However, the preferred location inside ANT is not well known. In this study, we investigated the relationship between stereotactical coordinates of stimulated contacts and clinical improvement, in order to define the ideal target for ANT-DBS. Methods: Individual contact’s coordinates were obtained in the Montreal Neurological Institute (MNI) 152 space, with the utilization of advanced normalization tools and co-registration of pre- and postoperative MRI and CT images in open-source toolbox lead-DBS with the “Atlas of the Human Thalamus.” Each contact’s pair was either classified as a responder (≥50% seizure reduction and absence of intolerable adverse effects) or nonresponder, with a minimum follow-up of 11 continuous months of stimulation. Results: A total of 19 contacts’ pairs were tested in 14 patients. The responder rate was 9 out of 14 patients (64.3%). In 4 patients, a change in contacts’ pairs was needed to achieve this result. A highly encouraging location inside ANT (HELIA) was delimited in MNI space, corresponding to an area in the anterior and inferior portion of the anteroventral (AV) nucleus, medially to the endpoint of the mammillothalamic tract (ANT-mtt junction) (x [3.8; 5.85], y [−2.1; −6.35] and z [6.2; 10.1] in MNI space). Statistically significant difference was observed between responders and nonresponders, in terms of the number of coordinates inside this volume. Seven responders and two nonresponders had at least 5 of 6 coordinates (2 electrodes) inside HELIA (77.8% sensitivity and 80% specificity). In 3 patients, changing to contacts that were better placed inside HELIA changed the status from nonresponder to responder. Conclusions: A relationship between stimulated contacts’ coordinates and responder status was observed in drug-resistant epilepsy. The possibility to target different locations inside HELIA may help surpass anatomical variations and eventually obtain increased clinical benefit.

Quantitative magnetic resonance imaging for segmentation and white matter extraction of the hypothalamus.

Since the hypothalamus is involved in many neuroendocrine, metabolic, and affective disorders, detailed hypothalamic imaging has become of major interest to better characterize disease-induced tissue damages and abnormalities. Still, image contrast of conventional anatomical magnetic resonance imaging lacks morphological detail, thus complicating complete and precise segmentation of the hypothalamus. The hypothalamus' position lateral to the third ventricle and close proximity to white matter tracts including the optic tract, fornix, and mammillothalamic tract display one of the remaining shortcomings of hypothalamic segmentation, as reliable exclusion of white matter is not yet possible. Recent studies found that quantitative magnetic resonance imaging (qMRI), a method to create maps of different standardized tissue contents, improved segmentation of cortical and subcortical brain regions. So far, this has not been tested for the hypothalamus. Therefore, in this study, we investigated the usability of qMRI and diffusion MRI for the purpose of detailed and reproducible manual segmentation of the hypothalamus and data-driven white matter extraction and compared our results to recent state-of-the-art segmentations. Our results show that qMRI presents good contrast for delineation of the hypothalamus and white matter, and that the properties of these images differ between subunits, such that they can be used to reliably exclude white matter from hypothalamic tissue. We propose that qMRI poses a useful addition to detailed hypothalamic segmentation and volumetry.

Deep Brain Stimulation in Epilepsy: A Role for Modulation of the Mammillothalamic Tract in Seizure Control?

Schaper, Frédéric L W V J MD; Plantinga, Birgit R PhD; Colon, Albert J MD, PhD; Wagner, G Louis MD; Boon, Paul MD, PhD; Blom, Nadia MSc; Gommer, Erik D PhD; Hoogland, Govert PhD; Ackermans, Linda MD, PhD; Rouhl, Rob P W MD, PhD; Temel, Yasin MD, PhD Author Information

P.175 Direct Visualization of Thalamic Nuclei using 7 Tesla MRI and quantification in patients with temporal lobe epilepsy.

Background: Most individual thalamic nuclei cannot be directly visualized on routine clinical MRI. Stereotactic targeting techniques are indirect, relying on histological atlases and electrophysiological recording. We investigate whether high-field MRI can directly visualize the thalamic nuclei in vivo and allow for analysis of disease-related changes. Methods: Thirty-two healthy individuals were imaged with 7T MRI at a resolution of 0.7mm3. To obtain a high-resolution composite image, these were registered across subjects and averaged together. Three thalamic structures closely integrated in seizure propagation, the anterior thalamic nucleus (ATN), mammillothalamic tract (MTT), and centromedian nucleus (CM) were manually segmented in a subset of healthy subjects and patients with temporal lobe epilepsy (TLE). Results: There is sufficient resolution within the thalamus at 7T for visualization of the ATN, CM, and MTT. In the small subset of 5 controls and 5 TLE patients examined, there was no significant difference (p&gt;0.05) in volume or mean T1map for the three thalamic sturctures of interest. Conclusions: MRI at 7T provides a method of direct visualization of thalamic nuclei, uncovering substructures not previously identifiable in vivo. These advances will enable quantitative analysis of disease-related changes to these structures and improved clinical targeting as demonstrated in this initial ‘proof-of-concept’ subset analysis.

Analysis of Deep Brain Stimulation Lead Targeting in the Stimulation of Anterior Nucleus of the Thalamus for Epilepsy Clinical Trial.

BACKGROUNDDeep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an effective therapy for patients with drug-resistant focal epilepsy. Best practices for surgical targeting of the ANT can be refined as new information becomes available regarding effective stimulation sites.OBJECTIVETo conduct a retrospective analysis of the relationship between outcomes (seizure reduction during year 1) and DBS lead locations in subjects from the SANTÉ pivotal trial (Stimulation of ANT for Epilepsy) based upon recent clinical findings.METHODSPostoperative images from SANTÉ subjects (n = 101) were evaluated with respect to lead trajectory relative to defined anatomic landmarks. A qualitative scoring system was used to rate each lead placement for proximity to an identified target region above the junction of the mammillothalamic tract with the ANT. Each subject was assigned a bilateral lead placement score, and these scores were then compared to clinical outcomes.RESULTSApproximately 70% of subjects had “good” bilateral lead placements based upon location with respect to the defined target. These subjects had a much higher probability of being a clinical responder (>50% seizure reduction) than those with scores reflecting suboptimal lead placements (43.5% vs 21.9%, P < .05).CONCLUSIONConsistent with experience from more established DBS indications, our findings and other recent reports suggest that there may be specific sites within the ANT that are associated with superior clinical outcomes. It will be important to continue to evaluate these relationships and the evolution of other clinical practices (eg, programming) to further optimize this therapy.

Surgical targeting of large hypothalamic hamartomas and seizure-freedom following MR-guided laser interstitial thermal therapy

BackgroundLarge hypothalamic hamartomas (HH) are often associated with difficult-to-treat, refractory seizures. Although magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) has emerged as a useful tool to treat these challenging lesions, postoperative outcomes are variable and potentially related to differences in surgical targeting. PurposeWe sought to identify differences in the anatomic localization of laser ablations that either did or did not result in seizure freedom. MethodsFour children who underwent MRgLITT for large HH (3 seizure-free and 1 not seizure-free) were included in the analysis. Ablation volumes were segmented, normalized, and overlaid on a high-resolution hypothalamic atlas. For each lesion, the size, spatial extent, and degree of overlap with key hypothalamic nuclei and surrounding brain regions were computed and compared between ablations that did and did not result in seizure freedom. ResultsAblation masks that resulted in seizure freedom were smaller and located more centrally than the ablation mask that did not. In addition, ablation masks that resulted in seizure freedom overlapped with regions including the paraventricular nucleus, the posterior hypothalamus and the zona incerta, fornix, and mammillothalamic tract, whereas the single non-seizure-free ablation did not. ConclusionDifferences in the size, position, and anatomical localization of ablation volumes may be a potential contributor to the variability in postoperative outcomes of large HH treated with MRgLITT. A novel, high-resolution MRI atlas of the hypothalamus identifies a number of regions at the interface of large HH that are preferentially disconnected in seizure-free patients. This method of anatomical localization not only serves as a potential clinical tool for surgical targeting but may also provide novel insights into the mechanisms of epileptogenesis in hypothalamic hamartomas.

Anterior thalamic nuclei neurons sustain memory.

A hippocampal-diencephalic-cortical network supports memory function. The anterior thalamic nuclei (ATN) form a key anatomical hub within this system. Consistent with this, injury to the mammillary body-ATN axis is associated with examples of clinical amnesia. However, there is only limited and indirect support that the output of ATN neurons actively enhances memory. Here, in rats, we first showed that mammillothalamic tract (MTT) lesions caused a persistent impairment in spatial working memory. MTT lesions also reduced rhythmic electrical activity across the memory system. Next, we introduced 8.5 Hz optogenetic theta-burst stimulation of the ATN glutamatergic neurons. The exogenously-triggered, regular pattern of stimulation produced an acute and substantial improvement of spatial working memory in rats with MTT lesions and enhanced rhythmic electrical activity. Neither behaviour nor rhythmic activity was affected by endogenous stimulation derived from the dorsal hippocampus. Analysis of immediate early gene activity, after the rats foraged for food in an open field, showed that exogenously-triggered ATN stimulation also increased Zif268 expression across memory-related structures. These findings provide clear evidence that increased ATN neuronal activity supports memory. They suggest that ATN-focused gene therapy may be feasible to counter clinical amnesia associated with dysfunction in the mammillary body-ATN axis.