Injury to the circuit of Papez: An overlooked cause of recurrent seizures.

Key Clinical Message: Papez' circuit is a unique neural pathway in the limbic system that is correlated with seizure activity. Injuries affecting Papez' circuit are often small and unusual in location but can be identifiable in MRI and functional imaging modalities, which can be helpful in the workup of refractory epilepsy. Abstract: The Papez circuit is a unique neural pathway in the limbic system of the brain. We review a patient presenting with recurrent seizures as the main manifestation of Papez' circuit pathology. The radiologic features of ischemia involving the mammillothalamic tract in Papez' circuit were correlated with the seizure activity.

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.

"Vascular" Korsakoff Syndrome With Bilaterally Damaged Mammillothalamic Tracts: Insights Into the Pathogenesis of "Acute" Korsakoff Syndrome As Acute-Onset Irreversible Anterograde Amnesia.

The structural pathogenesis of Wernicke-Korsakoff syndrome remains debatable. Wernicke encephalopathy is acute and often reversible whereas Korsakoff syndrome (KS) is chronic and may be irreversible. The cognitive deficits observed in KS are considered to be primarily due to damage to the anterior nucleus of the thalamus, mammillary bodies, and corpus callosum. We present an extremely rare case of non-alcoholic "vascular" KS (vKS) as acute-onset amnesia. A 97-year-old man living alone was brought to our hospital, complaining of sudden-onset behavioral changes with amnesia. Diffusion-weighted images (DWIs) showed fresh cerebral infarction in the right thalamus involving the right mammillothalamic tract (MTT). T2*-weighted images (T2*WIs), in addition, revealed a microbleed scar over the left MTT. This case supports the hypothesis that bilateral MTT dysfunction can lead to KS. Furthermore, in collaboration with a prior report about non-alcoholic "acute" KS due to cerebral infarction, this case supports the existence of vascular KS as an acute-onset amnestic syndrome, as well as insight into the pathogenesis of KS as an irreversible amnestic syndrome.

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

BACKGROUND: Deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) can improve seizure control for patients with drug-resistant epilepsy (DRE). Yet, one cannot overlook the high discrepancy in efficacy among patients, possibly resulting from differences in stimulation site. OBJECTIVE: To test the hypothesis that stimulation at the junction of the ANT and mammillothalamic tract (ANT-MTT junction) increases seizure control. METHODS: The relationship between seizure control and the location of the active contacts to the ANT-MTT junction was investigated in 20 patients treated with ANT-DBS for DRE. Coordinates and Euclidean distance of the active contacts relative to the ANT-MTT junction were calculated and related to seizure control. Stimulation sites were mapped by modelling the volume of tissue activation (VTA) and generating stimulation heat maps. RESULTS: After 1 yr of stimulation, patients had a median 46% reduction in total seizure frequency, 50% were responders, and 20% of patients were seizure-free. The Euclidean distance of the active contacts to the ANT-MTT junction correlates to change in seizure frequency (r2 = 0.24, P = .01) and is ∼30% smaller (P = .015) in responders than in non-responders. VTA models and stimulation heat maps indicate a hot-spot at the ANT-MTT junction for responders, whereas non-responders had no evident hot-spot. CONCLUSION: Stimulation at the ANT-MTT junction correlates to increased seizure control. Our findings suggest a relationship between the stimulation site and therapy response in ANT-DBS for epilepsy with a potential role for the MTT. DBS directed at white matter merits further exploration for the treatment of epilepsy.

Ex vivo diffusion-weighted MRI tractography of the Göttingen minipig limbic system.

The limbic system encompasses a collection of brain areas primarily involved in higher cognitive and emotional processing. Altered function in the limbic circuitry may play a major role in various psychiatric disorders. This study aims to provide a high-quality ex vivo diffusion-weighted MRI (DWI) tractographic overview of the Göttingen minipig limbic system pathways, which are currently not well described. This may facilitate future translational large animal studies. The study used previously obtained post-mortem DWI scans in 3 female Göttingen minipigs aging 11-15 months. The tractography performed on the DWI data set was made using a probabilistic algorithm, and regions of interest (ROIs) were defined in accordance with a histological atlas. The investigated pathways included the fornix, mammillothalamic tract, stria terminalis, stria medullaris, habenulo-interpeduncular tract, and cingulum. All the investigated limbic connections could be visualized with a high detail yielding a comprehensive three-dimensional overview, which was emphasized by the inclusion of video material. The minipig limbic system pathways displayed using tractography closely resembled what was previously described in both human studies and neuronal tracing studies from other mammalian species. We encountered well-known inherent methodological challenges of tractography, e.g., partial volume effects and complex white matter regions, which may have contributed to derouted false-positive streamlines and the failure to visualize some of the minor limbic pathway ramifications. This underlines the importance of preexisting anatomical knowledge. Conclusively, we have, for the first time, provided an overview and substantial insight of the Göttingen minipig limbic system.

Significant Injury of the Mammillothalamic Tract without Injury of the Corticospinal Tract After Aneurysmal Subarachnoid Hemorrhage: A Retrospective Diffusion Tensor Imaging Study.

OBJECTIVE: Little is known about the pathophysiologic mechanisms of white matter injury after aneurysmal subarachnoid hemorrhage (aSAH). The purpose of this study is to investigate whether the mammillothalamic tract (MTT) or corticospinal tract (CST) is more affected by aSAH in the same patients with good outcome (Grade 5 on Glasgow Outcome Scale at 3 months) using diffusion tensor imaging (DTI). METHODS: Between June 2013 and September 2016, 21 patients with aSAH with good outcome and 21 sex- and age-matched normal healthy control participants were recruited. DTI was obtained at 8.92 ± 2.4 weeks after onset. Moreover, reconstruction of the CST and the MTT was completed with DTI-studio software. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values were measured. In addition, the motricity index and Mini-Mental State Examination scores were obtained. RESULTS: There was no statistically significant difference detected in the ADC and FA values of the CST between the patient and control groups (P > 0.05). On the contrary, there was a statistically significant difference in ADC and FA values of the MTT between the patient and control groups (P < 0.05). In addition, in the patient group, no correlation (P > 0.05) was observed between motricity index scores and DTI parameters (ADC and FA), whereas the Mini-Mental State Examination showed a positive correlation with FA (r = 0.591, P = 0.029) without correlation to ADC (r = 0.142, P = 0.628). CONCLUSIONS: Patients with good outcomes (Grade 5 on Glasgow Outcome Scale at 3 months) after aSAH appeared to suffer an injury of the MTT without an associated injury of the CST compared with the control group. This injury showed a correlation with cognitive dysfunction.

Neurosurgical relevance of the dissection of the diencephalic white matter tracts using the Klingler technique.

OBJECTIVE: The Klingler fiber dissection technique is a relevant and reliable method for neurosurgery to identify with accuracy the fine structure of the brain anatomy highlighting white matter tracts. In order to demonstrate the significance of the application of this technique, we aimed to observe the course and relations of the mammillothalamic and habenulo-interpeduncular tracts as there are very few papers showing these important diencephalic tracts. MATERIAL AND METHODS: Twelve formalin-fixed brains were dissected using the Klingler technique in order to expose the medial diencephalic surface. Diencephalic white matter tracts, particularly the mammillothalamic and habenulo-interpeduncular tracts, were dissected using wooden spatulas and metallic dissectors with different sizes and tips. Several measurements were performed in both dissected hemispheres relative to the mammillothalamic and habenulo-interpeduncular tracts. RESULTS: The course and length of these two tracts were visualized and the relations with other fiber systems and with the neighboring gray matter structures quantified and registered. The mammillothalamic tract approximately marks the anteroposterior coordinate of the anterior pole of the subthalamic nucleus in the anterior commissure - posterior commissure plane. CONCLUSION: The present study helps to understand the three-dimensional architecture of the white matter systems of tracts when the Klingler technique is used. The numerical data obtained may be helpful to neurosurgeons while approaching brain paraventricular and ventricular lesions and deep brain stimulation. Finally, the anatomical knowledge can lower surgical complications and improve patient care particularly in the field of neurosurgery.

The importance of mammillary body efferents for recency memory: towards a better understanding of diencephalic amnesia.

Despite being historically one of the first brain regions linked to memory loss, there remains controversy over the core features of diencephalic amnesia as well as the critical site for amnesia to occur. The mammillary bodies and thalamus appear to be the primary locus of pathology in the cases of diencephalic amnesia, but the picture is complicated by the lack of patients with circumscribed damage. Impaired temporal memory is a consistent neuropsychological finding in Korsakoff syndrome patients, but again, it is unclear whether this deficit is attributable to pathology within the diencephalon or concomitant frontal lobe dysfunction. To address these issues, we used an animal model of diencephalic amnesia and examined the effect of mammillothalamic tract lesions on tests of recency memory. The mammillothalamic tract lesions severely disrupted recency judgements involving multiple items but left intact both recency and familiarity judgements for single items. Subsequently, we used disconnection procedures to assess whether this deficit reflects the indirect involvement of the prefrontal cortex. Crossed-lesion rats, with unilateral lesions of the mammillothalamic tract and medial prefrontal cortex in contralateral hemispheres, were unimpaired on the same recency tests. These results provide the first evidence for the selective importance of mammillary body efferents for recency memory. Moreover, this contribution to recency memory is independent of the prefrontal cortex. More broadly, these findings identify how specific diencephalic structures are vital for key elements of event memory.

Assessment of Age-Related Morphometric Changes of Subcortical Structures in Healthy People Using Ultra-High Field 7 Tesla Magnetic Resonance Imaging.

Objective: To assess the age-related morphometric changes of subcortical structures in healthy people. Materials and Methods: Ultra-high field 7 tesla magnetic resonance (MR) imaging in humans was used to visualize the subcortical structures of healthy young, middle-aged and elderly participants. Using the magnetization-prepared two rapid acquisition gradient echo (MP2RAGE) sequence, we assessed the visibility of the margins of the thalamus and white matter in the thalamus, as well as the anterior commissure (AC) and posterior commissure (PC) length, the maximal height of the thalamus, the half width of the third ventricle and the distance between the AC and the center of the mammillothalamic tract (MTT) at the level of the AC-PC plane. All quantitative data were statistically evaluated. Results: The AC-PC length did not differ significantly among the three groups. The maximal height of the thalamus decreased with age (rs(53) = -0.719, p < 0.001). The half width of the third ventricle (rs(53) = 0.705, p < 0.001) and the distance between the AC and the center of the MTT (rs(53) = 0.485, p < 0.001) increased with age. The distance between the AC and the center of the MTT of the young and the elderly participants differed significantly (p = 0.007). Conclusion: The AC-PC length is not a good candidate for proportional correction during atlas-to-patient registration. The maximal height of the thalamus and the half width of the third ventricle correlated strongly with age, and the MTT position in relation to the AC shifted posteriorly as age increased. These age-related morphometric changes of subcortical structures should be considered in targeting for functional neurosurgery.

Acute Amnesia due to Isolated Mammillary Body Infarct.

BACKGROUND: There are limited reports describing acute amnesia after mammillothalamic tract infarction. Furthermore, acute infarction isolated to the mammillary body has never been reported. We present the first case of anterograde amnesia after isolated acute infarction of the mammillary body in a patient without concurrent or prior thalamic or mammillothalamic tract injury. METHODS: A retrospective review of the patient's electronic medical record including inpatient notes and all radiological examinations was performed. RESULTS: A 50-year-old woman presented with acute onset of confusion and constant repetition of the same questions. Magnetic resonance (MR) imaging of the brain showed isolated acute infarct of the left mammillary body without concurrent abnormality of the thalamus or mammillothalamic tract. MR angiography showed severe stenosis of the proximal posterior cerebral artery at the origin of the perforating mammillary artery. CONCLUSIONS: Isolated injury to the mammillary body is rare. In addition to recognized memory-related structures such as the thalamus and mammillothalamic tract, mammillary body injury may also play a role in memory dysfunction. Knowledge of the vascular supply of memory-related structures is important in diagnosing and understanding memory dysfunction.

Anterior nuclear deep brain stimulation guided by concordant hippocampal recording.

OBJECT: Anterior nuclear (AN) stimulation has been reported to reduce the frequency of seizures, in some cases dramatically; however, it has not been approved by the US Food and Drug Administration. The anterior nucleus is difficult to target because of its sequestered location, partially surrounded by the ventricle. It has traditionally been targeted by using transventricular or lateral transcortical routes. Here, the authors report a novel approach to targeting the anterior nucleus and neurophysiologically confirming effective stimulation of the target, namely evoked potentials in the hippocampus. METHODS: Bilateral AN 3389 electrodes were placed in a novel trajectory followed by bilateral hippocampal 3391 electrodes from a posterior trajectory. Each patient was implanted bilaterally with a Medtronic Activa PC+S device under an investigational device exemption approval. Placement was confirmed with CT. AN stimulation-induced hippocampal evoked potentials were measured to functionally confirm placement in the anterior nucleus. RESULTS: Two patients had implantations by way of a novel AN trajectory with concomitant hippocampal electrodes. There were no lead misplacements. Postoperative stimulation of the anterior nucleus with a PC+S device elicited evoked potentials in the hippocampus. Thus far, both patients have reported a > 50% improvement in seizure frequency. CONCLUSIONS: Placing AN electrodes posteriorly may provide a safer trajectory than that used for traditionally placed AN electrodes. In addition, with a novel battery that is capable of electroencephalographic recording, evoked potentials can be used to functionally assess the Papez circuit. This treatment paradigm may offer increased AN stimulation efficacy for medically intractable epilepsy by assessing functional placement more effectively and thus far has proven safe.

The mammillary bodies and memory: more than a hippocampal relay.

Although the mammillary bodies were one of the first neural structures to be implicated in memory, it has long been assumed that their main function was to act primarily as a hippocampal relay, passing information on to the anterior thalamic nuclei and from there to the cingulate cortex. This view not only afforded the mammillary bodies no independent role in memory, it also neglected the potential significance of other, nonhippocampal, inputs to the mammillary bodies. Recent advances have transformed the picture, revealing that projections from the tegmental nuclei of Gudden, and not the hippocampal formation, are critical for sustaining mammillary body function. By uncovering a role for the mammillary bodies that is independent of its subicular inputs, this work signals the need to consider a wider network of structures that form the neural bases of episodic memory.

How do mammillary body inputs contribute to anterior thalamic function?

It has long been assumed that the main function of the mammillary bodies is to provide a relay for indirect hippocampal inputs to the anterior thalamic nuclei. Such models afford the mammillary bodies no independent role in memory and overlook the importance of their other, non-hippocampal, inputs. This review focuses on recent advances that herald a new understanding of the importance of the mammillary bodies, and their inputs from the limbic midbrain, for anterior thalamic function. It has become apparent that the mammillary bodies' contribution to memory is not dependent on afferents from the subicular complex. Rather, the ventral tegmental nucleus of Gudden is a vital source of inputs that support memory processes within the medial mammillary bodies. In parallel, the lateral mammillary bodies, via their connections with the dorsal tegmental nucleus of Gudden, are critical for generating head-direction signals. These two parallel, but distinct, information streams converge on the anterior thalamic nuclei and support different aspects of spatial memory.

Accelerated forgetting of contextual details due to focal medio-dorsal thalamic lesion.

Effects of thalamic nuclei damage and related white matter tracts on memory performance are still debated. This is particularly evident for the medio-dorsal thalamus which has been less clear in predicting amnesia than anterior thalamus changes. The current study addresses this issue by assessing 7 thalamic stroke patients with consistent unilateral lesions focal to the left medio-dorsal nuclei for immediate and delayed memory performance on standard visual and verbal tests of anterograde memory, and over the long-term (>24 h) on an object-location associative memory task. Thalamic patients showed selective impairment to delayed recall, but intact recognition memory. Patients also showed accelerated forgetting of contextual details after a 24 h delay, compared to controls. Importantly, the mammillothalamic tract was intact in all patients, which suggests a role for the medio-dorsal nuclei in recall and early consolidation memory processes.

Injury of the mammillothalamic tract in patients with thalamic hemorrhage.

OBJECTIVE: Injury of the mammillothalamic tract (MTT) has been suggested as one of the plausible pathogenic mechanisms of memory impairment in patients with thalamic hemorrhage; however, it has not been clearly demonstrated so far. We attempted to investigate whether injury of the MTT documented by diffusion tensor tractography following thalamic hemorrhage correlates with cognitive impairment. METHODS: We recruited 22 patients with a thalamic hemorrhage and 20 control subjects. MTTs were reconstructed using the probabilistic tractography method. Patients were classified into two subgroups: reconstructed group, patients whose MTT was reconstructed in the affected hemisphere, and non-reconstructed group, patients whose MTT was not reconstructed. RESULTS: Mammillothalamic tract was reconstructed in 5 (22.7%, reconstructed group) patients in the affected hemisphere and was not reconstructed in the remaining 17 patients (77.3%, non-reconstructed group). In addition, the MTT was not reconstructed even in the unaffected hemisphere in four patients (23.5%) in non-reconstructed group. Fractional anisotropy and mean diffusivity values of the affected hemisphere in reconstructed group also did not show significant differences from those in the unaffected hemisphere of reconstructed group and the control group (p > 0.05). However, the tract volume of the affected hemisphere in reconstructed group was significantly lower than that of the unaffected hemisphere in reconstructed group and the control group (p < 0.05). CONCLUSION: A large portion of patients with thalamic hemorrhage appeared to suffer severe injury of the ipsilesional MTT (77.3%) and 18.2% of them appeared to suffer severe injury even in the contralesional MTT. In addition, the remaining 22.7% of patients who had preserved integrity of the ipsilesional MTT appeared to suffer partial injury of the ipsilesional MTT.

Colocalization pattern of calbindin and cocaine- and amphetamine-regulated transcript in the mammillary body-anterior thalamic nuclei axis of the guinea pig.

The study describes for the first time the colocalization pattern of calbindin (CB) and cocaine- and amphetamine-regulated transcript (CART) in the mammillary body (MB) and anterior thalamic nuclei (ATN) - structures connected in a topographically organized manner by the mammillothalamic tract (mtt). Immunohistochemical study was performed on fetal (E40, E50, E60), newborn (P0) and postnatal (P20, P80) brains of the guinea pig, but the coexistence pattern of the substances was invariable throughout the examined developmental stages. CB and CART colocalized in the perikarya of the lateral part of the medial mammillary nucleus (MMl), whereas in its medial part (MMm) only CB was detected. In the mtt, which originates from the MB, both the substances were present and colocalized in single fibers. Next, fibers from the mtt spread toward the ATN in a particular way: fibers containing CB ran to both the anteromedial thalamic nucleus (AM) and anteroventral thalamic nucleus (AV), while fibers containing CART ran mostly to the latter one. In the ventral part of AV, CB and CART colocalized vastly in the neuropil. The lateral mammillary nucleus and anterodorsal thalamic nucleus were virtually devoid of CB- and CART-positive structures. Based on the known connections between the MB and ATN, we conclude that the studied substances may cooperate in the MMl-AV part of the axis and CB plays a significant role in the MMm-AM part.

Visualization of intra-thalamic nuclei with optimized white-matter-nulled MPRAGE at 7T.

Novel MR image acquisition strategies have been investigated to elicit contrast within the thalamus, but direct visualization of individual thalamic nuclei remains a challenge because of their small size and the low intrinsic contrast between adjacent nuclei. We present a step-by-step specific optimization of the 3D MPRAGE pulse sequence at 7T to visualize the intra-thalamic nuclei. We first measured T1 values within different sub-regions of the thalamus at 7T in 5 individuals. We used these to perform simulations and sequential experimental measurements (n=17) to tune the parameters of the MPRAGE sequence. The optimal set of parameters was used to collect high-quality data in 6 additional volunteers. Delineation of thalamic nuclei was performed twice by one rater and MR-defined nuclei were compared to the classic Morel histological atlas. T1 values within the thalamus ranged from 1400ms to 1800ms for adjacent nuclei. Using these values for theoretical evaluations combined with in vivo measurements, we showed that a short inversion time (TI) close to the white matter null regime (TI=670ms) enhanced the contrast between the thalamus and the surrounding tissues, and best revealed intra-thalamic contrast. At this particular nulling regime, lengthening the time between successive inversion pulses (TS=6000ms) increased the thalamic signal and contrast and lengthening the α pulse train time (N*TR) further increased the thalamic signal. Finally, a low flip angle during the gradient echo acquisition (α=4°) was observed to mitigate the blur induced by the evolution of the magnetization along the α pulse train. This optimized set of parameters enabled the 3D delineation of 15 substructures in all 6 individuals; these substructures corresponded well with the known anatomical structures of the thalamus based on the classic Morel atlas. The mean Euclidean distance between the centers of mass of MR- and Morel atlas-defined nuclei was 2.67mm (±1.02mm). The reproducibility of the MR-defined nuclei was excellent with intraclass correlation coefficient measured at 0.997 and a mean Euclidean distance between corresponding centers of mass found at first versus second readings of 0.69mm (±0.38mm). This 7T strategy paves the way to better identification of thalamic nuclei for neurosurgical planning and investigation of regional changes in neurological disorders.

Multiple thalamo-cortical disconnections in anterior thalamic infarction: implications for thalamic mechanisms of memory and language.

Amnesia and linguistic deficits that are associated with thalamic damage have attracted the attention of researchers interested in identifying the neural networks involved in memory and language. The Papez circuit, which is composed of the hippocampus, mammillary body and anterior thalamic nuclei, was first proposed to be critical for memory. However, subsequently, the roles of the neural circuit consisting of the rhinal/parahippocampal cortices and the mediodorsal thalamic nuclei became evident. The ventral lateral nuclei or its adjacent structures have been found to be involved in semantic processing, but the specific neural circuits dedicated to language functions have not been identified. Anterior thalamic infarcts, which affect very circumscribed regions of the ventral anterior portion of the thalamus, often cause paradoxically prominent memory and language deficits. We conducted tractography analyses in 6 patients with left anterior thalamic infarcts to identify neural connections or circuits in which disruptions are associated with memory and language deficits in this condition. The current study demonstrated that the mammillothalamic tract, which connects the mammillary body with the anterior thalamic nuclei, and the anterior and inferior thalamic peduncles, which contain neural fibers that extend from several thalamic nuclei to the anterior temporal, medial temporal and frontal cortices, are disrupted in anterior thalamic infarction. These extensive thalamo-cortical disconnections appear to be due to the dissection of the neural fibers that penetrate the ventral anterior nucleus of the thalamus. Our results suggest the following: (1) amnesia that is associated with anterior thalamic infarction is best interpreted in the context of dual/multiple-system theories of memory/amnesia that posit that multiple neural circuits connecting the anterior and mediodorsal thalamic nuclei with the hippocampus and rhinal/parahippocampal cortices work in concert to support memory function; and (2) the semantic deficits observed in this syndrome may be associated with thalamo-anterior temporal and thalamo-lateral frontal disconnections.