Mediodorsal Nucleus Research Articles

Depicting Primate-Like Granular Dorsolateral Prefrontal Cortex in the Chinese Tree Shrew.

It remains unknown whether the Chinese tree shrew, regarded as the closest sister of primate, has evolved a dorsolateral prefrontal cortex (dlPFC) comparable with primates that is characterized by a fourth layer (L4) enriched with granular cells and reciprocal connections with the mediodorsal nucleus (MD). Here, we reported that following AAV-hSyn-EGFP expression in the MD neurons, the fluorescence micro-optical sectioning tomography revealed their projection trajectories and targeted brain areas, such as the hippocampus, the corpus striatum, and the dlPFC. Cre-dependent transsynaptic viral tracing identified the MD projection terminals that targeted the L4 of the dlPFC, in which the presence of granular cells was confirmed via cytoarchitectural studies by using the Nissl, Golgi, and vGlut2 stainings. Additionally, the L5/6 of the dlPFC projected back to the MD. These results suggest that the tree shrew has evolved a primate-like dlPFC which can serve as an alternative for studying cognition-related functions of the dlPFC.

Microdosing of a kappa opioid receptor agonist within proximal nucleus accumbens shell microstructures revealing opposing behavioral outcomes

Targeted intracranial delivery of molecularly-specific therapies within intricate brain structures poses a formidable challenge due to the heterogeneity of neuronal phenotypes and functions. Here we report the use of an implantable, miniaturized neural drug delivery system permitting dynamic adjustment of pharmacotherapies. Specifically, we exploit the spatial accuracy afforded by this method for targeting modulation of neuronal microstructures. Kappa opioid receptors (KOR) within the dorsal medial nucleus accumbens shell (NASh) are selectively activated through micro infusions of the KOR agonist, U-50488. Remarkably, we demonstrate that micro infusions of U-50488 into the dorsal NASh induces reward-like conditioned place preferences, whereas a mere 1 mm shift ventrally results in conditioned place aversions. The striking precision afforded by this method may prove useful in other neurotherapeutic interventions.

Thalamocortical contributions to hierarchical cognitive control.

Cognitive flexibility relies on hierarchically structured task representations that organize task contexts, relevant environmental features, and subordinate decisions. Despite ongoing interest in the human thalamus, its role in cognitive control has been understudied. This study explored thalamic representation and thalamocortical interactions that contribute to hierarchical cognitive control in humans. We found that several thalamic nuclei, including the anterior, mediodorsal, ventrolateral, and pulvinar nuclei, exhibited stronger evoked responses when subjects switch between task contexts. Decoding analysis revealed that thalamic activity encodes task contexts within the hierarchical task representations. To determine how thalamocortical interactions contribute to task representations, we developed a thalamocortical functional interaction model to predict task-related cortical representation. This data-driven model outperformed comparison models, particularly in predicting activity patterns in cortical regions that encode context representations. Collectively, our findings highlight the significant contribution of thalamic activity and thalamocortical interactions for contextually guided hierarchical cognitive control.

Periaqueductal gray connectivity in spinal cord injury-induced neuropathic pain.

Neuropathic pain (NP) is a debilitating condition following spinal cord injury (SCI). The role of periaqueductal gray (PAG) in NP development following SCI remains underexplored. Using resting-state functional MRI (rsfMRI), our study aimed to demonstrate the alterations in functional connectivity (FC) of PAG in NP following SCI. Ten SCI patients (SCI+NP, n=7, and SCI-NP, n=3), alongside 10 healthy controls (HCs), were enrolled. rsfMRI was conducted followed by seed-to-voxel analysis using PAG as the seed region and then group-based analysis comprising three groups (SCI+NP, SCI-NP, and HC). Age and gender were considered as confounding variables. Compared to HCs, SCI+NP demonstrated decreased FC between PAG and right insula, right frontal orbital cortex, right pallidum, dorsal raphe nucleus (DRN), red nuclei (RN), substantia nigra (SN), and ventral posterolateral (VPL) thalamic nuclei. Compared to SCI-NP, SCI+NP demonstrated increased FC between PAG and posterior cingulate cortex (PCC), hippocampus, cerebellar vermis lobules IV and V, and thalamic structures (posterior and lateral pulvinar, the mediodorsal nuclei, and the ventral lateral nuclei). Additionally, decreased FC between the PAG and VPL, geniculate bodies, intralaminar nuclei of thalamus, DRN, RN, SN, and prefrontal cortex was observed in this comparison. Altered FC between PAG and right anterior insula, VPL, DRN, RN, SN, cerebellar vermis lobules IV and V, frontal cortex, and PCC was associated with NP sequelae of SCI. Additionally, SCI was independently associated with decreased FC between PAG and right posterior insula, cerebellar lobules IV and V, and cerebellar vermis lobules III, IV, and V.

Cross-species Convergence of Functional Connectivity Changes in Thalamic Pain across Human Patients and Model Macaques

Thalamic pain can be understood as a network reorganization disorder. This study aimed to investigate functional connectivity (FC) in human patients and a macaque model of thalamic pain. In humans, functional brain activity was compared between patients with thalamic pain and healthy individuals. Furthermore, functional brain activity was compared in macaques, before and after the induction of thalamic pain in the same individuals. FCs between the amygdala of the unaffected hemisphere and the brainstem was significantly higher in patients with thalamic pain. More specifically, a significant FC higher was observed between the basolateral amygdala (BLA) and the ventral tegmental area, which also significantly predicted the value of a visual analog scale of pain intensity in individual patients. The macaque model of thalamic pain also exhibited a significant FC higher between the amygdala of the unaffected hemisphere and the brainstem, particularly between the BLA and the midbrain. Furthermore, the previously reported significant FC higher between the amygdala and the mediodorsal nucleus of the thalamus in macaques with thalamic pain was also reproduced in the human patients. Therefore, the present results suggest that the FC changes in the regions associated with emotion, memory, motivation, and reward are part of the underlying mechanisms of thalamic pain onset present in both human patients and model macaques. This cross-species convergence provides new insights into the neurological mechanisms underlying thalamic pain, paving the way for further studies and the development of therapeutic strategies. PerspectiveThis article presents that the functional connectivity changes in the regions associated with emotion, motivation, and reward are part of the underlying mechanisms of thalamic pain in humans and macaques.

Neural Processing of Taste-Related Signals in the Mediodorsal Thalamus of Mice.

Our consummatory decisions depend on the taste of food and the reward experienced while eating, which are processed through neural computations in interconnected brain areas. Although many gustatory regions of rodents have been explored, the mediodorsal nucleus of the thalamus (MD) remains understudied. The MD, a multimodal brain area connected with gustatory centers, is often studied for its role in processing associative and cognitive information and has been shown to represent intraorally-delivered chemosensory stimuli after strong retronasal odor-taste associations. Key questions remain about whether MD neurons can process taste quality independently of odor-taste associations and how they represent extraoral signals predicting rewarding and aversive gustatory outcomes. Here, we present electrophysiological evidence demonstrating how mouse MD neurons represent and encode 1) the identity and concentrations of basic taste qualities during active licking, and 2) auditory signals anticipating rewarding and aversive taste outcomes. Our data reveal that MD neurons can reliably and dynamically encode taste identity in a broadly tuned manner and taste concentrations with spiking activity positively and negatively correlated with stimulus intensity. Our data also show that MD can represent information related to predictive cues and their associated outcomes, regardless of whether the cue predicts a rewarding or aversive outcome. In summary, our findings suggest that the mediodorsal thalamus is integral to the taste pathway, as it can encode sensory-discriminative dimensions of tastants and participate in processing associative information essential for ingestive behaviors.

Outcomes and Mechanisms Associated With Selective Thalamic Neuronal Loss in Chronic Traumatic Brain Injury

The chronic neuronal burden of traumatic brain injury (TBI) is not fully characterized by routine imaging, limiting understanding of the role of neuronal substrates in adverse outcomes. To determine whether tissues that appear healthy on routine imaging can be investigated for selective neuronal loss using [11C]flumazenil (FMZ) positron emission tomography (PET) and to examine whether this neuronal loss is associated with long-term outcomes. In this cross-sectional study, data were collected prospectively from 2 centers (University of Cambridge in the UK and Weill Cornell Medicine in the US) between September 1, 2004, and May 31, 2021. Patients with TBI (>6 months postinjury) were compared with healthy control participants (all aged >18 years). Individuals with neurological disease, benzodiazepine use, or contraindication to magnetic resonance imaging were excluded. Data were retrospectively collated with nonconsecutive recruitment, owing to convenience and scanner or PET ligand availability. Data were analyzed between February 1 and September 30, 2023. Flumazenil voxelwise binding potential relative to nondisplaceable binding potential (BPND). Selective neuronal loss identified with FMZ PET was compared between groups on voxelwise and regional scales, and its association with functional, cognitive, and psychological outcomes was examined using Glasgow Outcome Scale (GOS) scores, measures of sustained executive attention (animal and sustained fluency), and 36-Item Short Form Health Survey (SF-36) scores. Diffusion tensor imaging was used to assess structural connectivity of regions of cortical damage, and its association with thalamic selective neuronal loss. In this study, 24 patients with chronic TBI (mean [SD] age, 39.2 [12.3] years; 18 men [75.0%]) and 33 healthy control participants (mean [SD] age, 47.6 [20.5] years; 23 men [69.7%]) underwent FMZ PET. Patients with TBI had a median time of 29 (range, 7-95) months from injury to scan. They displayed selective neuronal loss in thalamic nuclei, over and above gross volume loss in the left thalamus, and bilateral central, mediodorsal, ventral-lateral dorsal, anterior, and ventral anterior thalamic nuclei, across a wide range of injury severities. Neuronal loss was associated with worse functional outcome using GOS scores (left thalamus, left ventral anterior, and bilateral central, mediodorsal, and anterior nuclei), worse cognitive outcome on measures of sustained executive attention (left thalamus, bilateral central, and right mediodorsal nuclei), and worse emotional outcome using SF-36 scores (right central thalamic nucleus). Chronic thalamic neuronal loss partially mirrored the location of primary cortical contusions, which may indicate secondary injury mechanisms of transneuronal degeneration. The findings of this study suggest that selective thalamic vulnerability may have chronic neuronal consequences with relevance to long-term outcome, suggesting the evolving and potentially lifelong thalamic neuronal consequences of TBI. FMZ PET is a more sensitive marker of the burden of neuronal injury than routine imaging; therefore, it could inform outcome prognostication and may lead to the development of individualized precision medicine approaches.

Normative Modeling of Thalamic Nuclear Volumes and Characterization of Lateralized Volume Alterations in Alzheimer’s Disease Versus Schizophrenia

BackgroundThalamic nuclei facilitate a wide range of complex behaviors, emotions, and cognition and have been implicated in neuropsychiatric disorders including Alzheimer’s disease (AD) and schizophrenia (SCZ). The aim of this work was to establish novel normative models of thalamic nuclear volumes and their laterality indices and investigate their changes in SCZ and AD. MethodsVolumes of bilateral whole thalami and 10 thalamic nuclei were generated from T1 magnetic resonance imaging data using a state-of-the-art novel segmentation method in healthy control participants (n = 2374) and participants with early mild cognitive impairment (n = 211), late mild cognitive impairment (n = 113), AD (n = 88), and SCZ (n = 168). Normative models for each nucleus were generated from healthy control participants while controlling for sex, intracranial volume, and site. Extreme z-score deviations (|z| > 1.96) and z-score distributions were compared across phenotypes. z Scores were associated with clinical descriptors. ResultsIncreased infranormal and decreased supranormal z scores were observed in SCZ and AD. z Score shifts representing reduced volumes were observed in most nuclei in SCZ and AD, with strong overlap in the bilateral pulvinar, medial dorsal, and centromedian nuclei. Shifts were larger in AD, with evidence of a left-sided preference in early mild cognitive impairment while a predilection for right thalamic nuclei was observed in SCZ. The right medial dorsal nucleus was associated with disorganized thought and daily auditory verbal hallucinations. ConclusionsIn AD, thalamic nuclei are more severely and symmetrically affected while in SCZ, the right thalamic nuclei are more affected. We highlight the right medial dorsal nucleus, which may mediate multiple symptoms of SCZ and is affected early in the disease course.

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.

Functional states of prelimbic and related circuits during the acquisition of a GO/noGO task in rats.

GO/noGO tasks enable assessing decision-making processes and the ability to suppress a specific action according to the context. Here, rats had to discriminate between 2 visual stimuli (GO or noGO) shown on an iPad screen. The execution (for GO) or nonexecution (for noGO) of the selected action (to touch or not the visual display) were reinforced with food. The main goal was to record and to analyze local field potentials collected from cortical and subcortical structures when the visual stimuli were shown on the touch screen and during the subsequent activities. Rats were implanted with recording electrodes in the prelimbic cortex, primary motor cortex, nucleus accumbens septi, basolateral amygdala, dorsolateral and dorsomedial striatum, hippocampal CA1, and mediodorsal thalamic nucleus. Spectral analyses of the collected data demonstrate that the prelimbic cortex was selectively involved in the cognitive and motivational processing of the learning task but not in the execution of reward-directed behaviors. In addition, the other recorded structures presented specific tendencies to be involved in these 2 types of brain activity in response to the presentation of GO or noGO stimuli. Spectral analyses, spectrograms, and coherence between the recorded brain areas indicate their specific involvement in GO vs. noGO tasks.

Amnesic Pathologies in Regulation of Dopamine as Supplement to Wernicke-Korsakoff Syndrome: A Limbic-Reticular Coupling View

Background: It was suggested by the limbic-reticular coupling theory that the hippocampus and amygdala regulate such descending limbic structures as the mammillary bodies, septum, hypothalamus and habenula, and in turn regulate the ascending noradrenergic, serotonergic, dopaminergic and cholinergic systems to consolidate and recall declarative memory, while the anterior and mediodorsal thalamic nuclei of Wernicke-Korsakoff syndrome beyond limbic-reticular coupling be related else to familiarity. Aim: It was aimed to highlight a portion of limbic-reticular coupling structures in alcoholic Korsakoff’s syndrome, including the dopaminergic system, habenula, mammillary bodies, etc. Methods: It was searched the papers from Pubmed and Baidu. Results and Discussions: It is highlighted that, (a) the mesolimbic dopamine, liable to be affected by alcohol, induces the hippocampal theta rhythm via septum, helping encode and consolidate new memories, such as dopaminergic enhancement of motivational declarative memory in young human adults; (b) dopamine can activate cortical gamma wave and help recall; (c) joint damage of habenula and mammillary bodies, both sending efferents to ventral tegmental area(VTA) rich in dopaminergic neurons, is sufficient to cause Korsakoff’s amnesia; (d) the loop of hippocampal CA3 to lateral septum(LS) to VTA(CA3-LS-VTA) activates dopamine for contextual memory in animals, consistent with dopaminergic antagonist impairing declarative memory recall in humans; (e) whereas thiamine deficiency, the major nutritional deficit causing Wernicke-Korsakoff syndrome, impairs noradrenergic but spares dopaminergic system. Conclusion: It is supplemented the integrative dysfunctions in regulation of such neglected dopaminergic system, including the habenula, mammillary bodies and VTA dopamine, as partial contribution to memory impairments in Korsakoff’s syndrome.

Antinociceptive role of the thalamic dopamine D3 receptor in descending modulation of intramuscular formalin-induced muscle nociception in a rat model of Parkinson's disease

Pain in Parkinson's disease (PD) has been validated as one of the major non-motor dysfunctions affecting the quality of life and subsequent rehabilitation. In the present study, we investigated the role of the dopamine D3 receptor in the thalamic mediodorsal (MD) and ventromedial (VM) nuclei mediated descending control of nociception and intramuscular (i.m.) 2.5% formalin-induced persistent muscle nociception. Paw withdrawal reflexes were measured in naive rats and rats subjected to PD induced by unilateral microinjection of 6 μg 6-OHDA into the rat striatum. Formalin-induced muscle nociception in phase 1, inter-phase, and phase 2 was significantly greater in PD rats compared to naive and vehicle-treated rats (P < 0.001). PD rats exhibited bilaterally mechanical hyperalgesia and heat hypoalgesia in formalin-induced muscle nociception. Microinjection of SK609, a dopamine D3 receptor agonist, at various doses (2.5–7.5 nmol/0.5 μl) into the thalamic VM nucleus dose-dependently prolonged heat-evoked paw withdrawal latencies in both naive and PD rats. Administration of SK609 to either the MD or VM nuclei had no effect on noxious mechanically evoked paw withdrawal reflexes. Pre-treatment of the thalamic MD nucleus with SK609 significantly attenuated formalin-induced nociception, and reversed mechanical hyperalgesia, but not heat hypoalgesia. Pre-treatment of the thalamic VM nucleus with SK609 inhibited formalin-induced nociception in the late phase of phase 2 (30–75 min) and heat hypoalgesia, but not mechanical hyperalgesia (P < 0.05). It is suggested that the dopamine D3 receptors in the thalamus play an antinociceptive role in the descending modulation of nociception. Activation of D3 receptors within the thalamic MD and VM nuclei attenuates descending facilitation and enhances descending inhibition in rats during PD.

Developmental Anatomy of Gray Matter of Spinal Cord in Animals with Special Reference to Prenatal Goat: A Review

Spinal cord is the major nerve tract of vertebrates, extending from the brain through the vertebral canal. Primordium, the neural tube was initially with thick lateral walls having three layers: inner germinal/ependymal layer, middle mantle layer forming the gray matter and outer marginal layer forming white matter. It presented a diamond-shaped lumen with a sulcus limitans, alar, basal, roof and floor plates and limiting membranes. Gray matter of the cord occupies the central region of spinal cord and in amniotes has in cross section, the well-known ‘H’ or butterfly-like shape. The white matter forms a thick peripheral zone of the cord and is divided by the gray columns into dorsal, lateral and ventral funiculi. There are three coumns for the gray matter, viz. the dorsal, ventral and lateral horns, with ventral ones being wider at the enlargements of the cord. Lateral horn appears only at thoracic, anterior lumbar and middle sacral levels. The layers of gray matter were laminae I to X. Lamina I or marginal zone capped the dorsal horn. Lamina II represented substantia gelatinosa and covered the dorsal horn, beneath marginal zone. Lamina III was an area with loosely arranged larger cells, entering the substantia gelatinosa. Lamina IV was a poorly defined cell column with nucleus proprius. Lamina V was a broad zone extending across the cervix of the dorsal horn; had spinal reticular nucleus and reticular processes. The region showed small to medium-sized cells which were most numerous in the zone between the ventral part of the dorsal horn and the lateral funiculus of white matter. Lamina VI was broad with unclear boundaries, related medially to central canal. It had compact medial and less compact lateral zones. Lamina VII shows the intermediate gray matter, with intermediolateral and intermediomedial nuclei, cervical nucleus of Stilling and Clark’s column. Lamina VIII had cells of small and medium size and was not sharply distinguished from lamina VII. Lamina IX had alpha and gamma type of neurons, which were larger at enlargements. Ventral horn had lateral and medial nuclear groups of multipolar neurons. Medial nuclear groups were seen in all regions and lateral groups only at enlargements. Medial nuclear group had dorsomedial and ventromedial nuclei; whereas the smaller lateral nuclear group had dorsolateral and ventrolateral nuclei. In addition, the enlargements also had central and retrodorsolateral nuclei. Lamina X was seen around the central canal. Laminae varied in cell size and thickness between regions of the cord. Development of laminae and nuclei of spinal gray in fetuses corresponded to the progressive growth of muscles and skeleton. All the ten laminae were together present in the spinal gray matter by the end of gestation.

Cholinergic deficiency in Parkinson's disease patients with visual hallucinations.

Visual hallucinations can increase the burden of disease for both patients with Parkinson's disease and their caregivers. Multiple neurotransmitters have been implicated in the neuropathology of visual hallucinations, which provide targets for treatment and prevention. In this study, we assessed the association between cholinergic denervation and visual hallucinations in Parkinson's disease in vivo, using PET imaging of the cholinergic system. A total of 38 patients with Parkinson's disease participated in this study. A group of 10 healthy subjects, matched for age, sex and education, was included for comparison. None of the participants used cholinergic drugs. Thirteen patients who had experienced visual hallucinations in the past month (VH+) were compared with 20 patients who had never experienced visual hallucinations in their lives (VH-). Cholinergic system integrity was assessed with PET imaging using 18F-fluoroethoxybenzovesamicol as the tracer. We assessed the differences in tracer uptake between groups by cluster-based analysis and by analysis of predefined regions of interest consisting of the ventral visual stream, the dorsal attentional network, the ventral attentional network and the lateral geniculate nucleus and mediodorsal nucleus of the thalamus. The Parkinson's disease group (n = 38) showed an extensive pattern of decreased tracer uptake throughout the brain compared with the controls (n = 10). Within the Parkinson's disease group, the VH+ group (n = 13) showed a cluster of decreased tracer uptake compared with the VH- group (n = 20), which covered most of the left ventral visual stream and extended towards superior temporal areas. These results were mirrored in the regions of interest-based analysis, in which the VH+ group showed the strongest deficits in the left inferior temporal gyrus and the left superior temporal gyrus compared with the VH- group. Visual hallucinations in Parkinson's disease are associated with a marked cholinergic deficiency in the left ventral visual stream and the left superior temporal lobe, in addition to an extensive global cholinergic denervation in the general Parkinson's disease population.

129 Neuroimaging Analysis of Bilateral Thalamic Delivery for Gene Therapy

INTRODUCTION: Axonal transport from the thalamus (an integrative hub for the entire cortex) has been shown to facilitate widespread gene/protein delivery. Here, we report our neuroimaging experience with bilateral thalamic convection-enhanced delivery of adeno-associated virus (AAV) vectors for GM2 gangliosidoses. METHODS: Magnetic resonance imaging (MRI) of eight pediatric patients who underwent bilateral thalamic HEXA/HEXB delivery were retrospectively reviewed. Quantitative three-dimensional volumetric analyses of MRI thalamic signals were used to establish volume of distribution (Vd) versus volume of infusion (Vi). The distance of cannula placement within the thalamus was calculated and validated using the numbers used in the intraoperative ROSA robotic software. Backflow and leakage into surrounding structures were also analyzed. RESULTS: Fourteen thalamic injection volumes were considered in the final analysis. Calculated volume of thalamic infusate signal was up to 43.8% (mean = 21.3±13.3) of the thalamic volume. The Vd/Vi ratio ranged from 0.4-2.7 (mean = 1.9±0.7), depending on infusate volume. Diffusate shape was round to slightly ellipsoid in all patients. Backflow and leakage were encountered in 14.3% and 12.5%, respectively, of thalamic injections. CONCLUSIONS: This study provides the first in-human quantitative MRI data for intrathalamic infusion. The ideal location for the cannula tip was determined to be between the mediodorsal and lateral dorsal nuclei and the ideal trajectory keeps all of the cannula steps within the thalamic boundaries. We also compare these data to published NHP and our own NHP and sheep data. Overall, the Vd/Vi ratios are lower in human subjects (∼2) than in animal subjects (∼3). We hypothesize that this may be due in part to species specific differences in displacement of extracellular fluid versus infusion volume.

353 Comparison of Brain Diffusion-Weighted Imaging of Cerebral Pain Regions Using DTI and MAP to Clinical Scores of Pain in Chronic Low Back Pain Patients Implanted With Thoracic Spinal Cord Stimulation

INTRODUCTION: Thoracic spinal cord stimulation (SCS) may be an effective treatment option for patients with chronic low back pain (cLBP), and pain levels can be assessed using subjective clinical scores. The use of diffusion-derived imaging of brain regions involved in pain has yet to be studied. METHODS: DTI and MAP data was gathered from five cLBP patients (4 M, 1F) post-tSCS scanned at a 3.0T scanner. Four DTI measures and four MAP measures were extracted and registered against a pain-ROI atlas. The following clinical pain scores were assessed in the same five patients: Numerical Pain Rating Scale (NPRS), Visual Analogue Scale (VAS), Central Sensitization Inventory (CSI), Oswestry Disability Index (ODI), Pain Catastrophizing Scale (PCS), Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression Scale (HADS). The associations between clinical scores and pain ROIs were investigated using linear regression. RESULTS: Within these eight measures, 16 significant linear associations were found between pain ROIs and clinical pain scores. The regions involved are areas of the cerebrum and thalamus involved in pain perception and processing: the secondary somatosensory cortex, the ventral posterolateral and mediodorsal nuclei of the thalamus, and the anterior long, anterior inferior, and middle short gyri of the insula. CONCLUSIONS: Diffusion-derived imaging, using DTI and AMURA/MAP techniques, shows microstructural changes in brain regions involved in pain with significant linear associations with clinical pain scores. As a result, diffusion-derived indices show potential to be used as a complementary quantitative measure to assess pain in cLBP patients receiving tSCS.

Neurogenetic underpinnings of nicotine use severity: Integrating the brain transcriptomes and GWAS variants via network approaches

Our study focused on human brain transcriptomes and the genetic risks of cigarettes per day (CPD) to investigate the neurogenetic mechanisms of individual variation in nicotine use severity. We constructed whole-brain and intramodular region-specific coexpression networks using BrainSpan's transcriptomes, and the genomewide association studies identified risk variants of CPD, confirmed the associations between CPD and each gene set in the region-specific subnetworks using an independent dataset, and conducted bioinformatic analyses. Eight brain-region-specific coexpression subnetworks were identified in association with CPD: amygdala, hippocampus, medial prefrontal cortex (MPFC), orbitofrontal cortex (OPFC), dorsolateral prefrontal cortex, striatum, mediodorsal nucleus of the thalamus (MDTHAL), and primary motor cortex (M1C). Each gene set in the eight subnetworks was associated with CPD. We also identified three hub proteins encoded by GRIN2A in the amygdala, PMCA2 in the hippocampus, MPFC, OPFC, striatum, and MDTHAL, and SV2B in M1C. Intriguingly, the pancreatic secretion pathway appeared in all the significant protein interaction subnetworks, suggesting pleiotropic effects between cigarette smoking and pancreatic diseases. The three hub proteins and genes are implicated in stress response, drug memory, calcium homeostasis, and inhibitory control. These findings provide novel evidence of the neurogenetic underpinnings of smoking severity.

Dementia risk and thalamic nuclei volumetry in healthy midlife adults: the PREVENT Dementia study.

A reduction in the volume of the thalamus and its nuclei has been reported in Alzheimer's disease, mild cognitive impairment and asymptomatic individuals with risk factors for early-onset Alzheimer's disease. Some studies have reported thalamic atrophy to occur prior to hippocampal atrophy, suggesting thalamic pathology may be an early sign of cognitive decline. We aimed to investigate volumetric differences in thalamic nuclei in middle-aged, cognitively unimpaired people with respect to dementia family history and apolipoprotein ε4 allele carriership and the relationship with cognition. Seven hundred participants aged 40-59 years were recruited into the PREVENT Dementia study. Individuals were stratified according to dementia risk (approximately half with and without parental dementia history). The subnuclei of the thalamus of 645 participants were segmented on T1-weighted 3 T MRI scans using FreeSurfer 7.1.0. Thalamic nuclei were grouped into six regions: (i) anterior, (ii) lateral, (iii) ventral, (iv) intralaminar, (v) medial and (vi) posterior. Cognitive performance was evaluated using the computerized assessment of the information-processing battery. Robust linear regression was used to analyse differences in thalamic nuclei volumes and their association with cognitive performance, with age, sex, total intracranial volume and years of education as covariates and false discovery rate correction for multiple comparisons. We did not find significant volumetric differences in the thalamus or its subregions, which survived false discovery rate correction, with respect to first-degree family history of dementia or apolipoprotein ε4 allele status. Greater age was associated with smaller volumes of thalamic subregions, except for the medial thalamus, but only in those without a dementia family history. A larger volume of the mediodorsal medial nucleus (Pfalse discovery rate = 0.019) was associated with a faster processing speed in those without a dementia family history. Larger volumes of the thalamus (P = 0.016) and posterior thalamus (Pfalse discovery rate = 0.022) were associated with significantly worse performance in the immediate recall test in apolipoprotein ε4 allele carriers. We did not find significant volumetric differences in thalamic subregions in relation to dementia risk but did identify an interaction between dementia family history and age. Larger medial thalamic nuclei may exert a protective effect on cognitive performance in individuals without a dementia family history but have little effect on those with a dementia family history. Larger volumes of posterior thalamic nuclei were associated with worse recall in apolipoprotein ε4 carriers. Our results could represent initial dysregulation in the disease process; further study is needed with functional imaging and longitudinal analysis.

Temporal association between sleep spindles and ripples in the human anterior and mediodorsal thalamus.

Sleep spindles are major oscillatory components of Non-Rapid Eye Movement (NREM) sleep, reflecting hyperpolarization-rebound sequences of thalamocortical neurons. Reports suggest a link between sleep spindles and several forms of high-frequency oscillations which are considered as expressions of pathological off-line neural plasticity in the central nervous system. Here we investigated the relationship between thalamic sleep spindles and ripples in the anterior and mediodorsal nuclei (ANT and MD) of epilepsy patients. Whole-night LFP from the ANT and MD were co-registered with scalp EEG/polysomnography by using externalized leads in 15 epilepsy patients undergoing a Deep Brain Stimulation protocol. Slow (~12 Hz) and fast (~14 Hz) sleep spindles were present in the human ANT and MD and roughly, 20% of them were associated with ripples. Ripple-associated thalamic sleep spindles were characterized by longer duration and exceeded pure spindles in terms of spindle power as indicated by time-frequency analysis. Furthermore, ripple amplitude was modulated by the phase of sleep spindles within both thalamic nuclei. No signs of pathological processes were correlated with measures of ripple and spindle association, furthermore, the density of ripple-associated sleep spindles in the ANT showed a positive correlation with verbal comprehension. Our findings indicate the involvement of the human thalamus in coalescent spindle-ripple oscillations of NREM sleep.

The Role of the Anterior Thalamic Nuclei in the Genesis of Memory Disorders in Alzheimer's Disease: An Exploratory Study.

Increasing evidence is demonstrating that degeneration of specific thalamic nuclei, in addition to the hippocampus, may occur in Alzheimer's disease (AD) from the prodromal stage (mild cognitive impairment - MCI) and contribute to memory impairment. Here, we evaluated the presence of macro and micro structural alterations at the level of the anterior thalamic nuclei (ATN) and medio-dorsal thalamic nuclei (MDTN) in AD and amnestic MCI (aMCI) and the possible relationship between such changes and the severity of memory impairment. For this purpose, a sample of 50 patients with aMCI, 50 with AD, and 50 age- and education-matched healthy controls (HC) were submitted to a 3-T MRI protocol with whole-brain T1-weighted and diffusion tensor imaging and a comprehensive neuropsychological assessment. At macro-structural level, both the ATN and MDTN were found significantly smaller in patients with aMCI and AD when compared to HC subjects. At micro-structural level, instead, diffusion alterations that significantly differentiated aMCI and AD patients from HC subjects were found only in the ATN, but not in the MDTN. Moreover, diffusion values of the ATN were significantly associated with poor episodic memory in the overall patients' group. These findings represent the first in vivo evidence of a relevant involvement of ATN in the AD-related neurodegeneration and memory profile and strengthen the importance to look beyond the hippocampus when considering neurological conditions characterized by memory decline.