NIBR-LTSi is a selective LATS kinase inhibitor activating YAP signaling and expanding tissue stem cells in vitro and in vivo.

The YAP/Hippo pathway is an organ growth and size regulation rheostat safeguarding multiple tissue stem cell compartments. LATS kinases phosphorylate and thereby inactivate YAP, thus representing a potential direct drug target for promoting tissue regeneration. Here, we report the identification and characterization of the selective small-molecule LATS kinase inhibitor NIBR-LTSi. NIBR-LTSi activates YAP signaling, shows good oral bioavailability, and expands organoids derived from several mouse and human tissues. In tissue stem cells, NIBR-LTSi promotes proliferation, maintains stemness, and blocks differentiation in vitro and in vivo. NIBR-LTSi accelerates liver regeneration following extended hepatectomy in mice. However, increased proliferation and cell dedifferentiation in multiple organs prevent prolonged systemic LATS inhibition, thus limiting potential therapeutic benefit. Together, we report a selective LATS kinase inhibitor agonizing YAP signaling and promoting tissue regeneration in vitro and in vivo, enabling future research on the regenerative potential of the YAP/Hippo pathway.

Generalized onset seizures with focal evolution (GOFE) - a largely unknown ictal variation in genetic generalized epilepsies.

PURPOSE: At onset of generalized seizures, focal electroclinical features are commonly seen, while generalized onset seizures with focal evolution (GOFE) are largely unknown bearing the risk of misclassification. METHODS: In two German epilepsy-centers, patients with GOFE documented by video-EEG monitoring (VEM) between 2017 and 2022 were identified retrospectively. In addition to analysis of ictal electroclinical features, detailed epilepsy and family history, response to antiseizure medication (ASM), and findings from neuroimaging were considered. RESULTS: We identified five patients with GOFE, three females, age 14 to 22 years. All patients developed genetic generalized epilepsy in childhood or adolescence, each presenting with two or three generalized seizure types. In each of the five patients, one GOFE was recorded by VEM. At onset, EEG seizure patterns were characterized by generalized spike-wave discharges at 2.5 to 3.5/sec for 9 to 16 s followed by focal evolution of the discharges. Interictally, all patients presented with generalized spike-wave discharges without focal abnormalities. Semiology at onset was behavioral arrest in two patients and generalized increase in tone in one, while two onsets were clinically inapparent. Semiological signs during focal evolution were variable, comprising head and body version, figure 4 sign, unilateral arm clonic activity, and staring with oral automatisms. In one case, focality involved both hemispheres successively. CONCLUSION: Prominent focal semiological features in GOFE carry a high risk of misclassification as focal seizures and epilepsy and thus wrong choice of ASM. This calls for low-threshold VEM if any doubts of focal genesis of seizures exist.

Screening for mitochondrial function before use-routine liver assessment during hypothermic oxygenated perfusion impacts liver utilization.

BACKGROUND: To report on a concept of liver assessment during ex situ hypothermic oxygenated perfusion (HOPE) and its significant impact on liver utilization. METHODS: An analysis of prospectively collected data on donation after circulatory death (DCD) livers, treated by HOPE at our institution, during a 11-year period between January 2012 and December 2022. FINDINGS: Four hundred and fifteen DCD Maastricht III livers were offered during the study period in Switzerland, resulting in 249 liver transplants. Of those, we performed 158 DCD III liver transplants at our institution, with 1-year patient survival and death censored graft survival (death with functioning graft) of 87 and 89%, respectively, thus comparable to benchmark graft survivals of ideal DBD and DCD liver transplants (89% and 86%). Correspondingly, graft loss for primary non-function or cholangiopathy was overall low, i.e., 7/158 (4.4%) and 11/158 (6.9%), despite more than 82% of DCD liver grafts ranked high (6-10 points) or futile risk (>10 points) according to the UK-DCD score. Consistently, death censored graft survival was not different between low-, high-risk or futile DCD III livers. The key behind these achievements was the careful development and implementation of a routine perfusate assessment of mitochondrial biomarkers for injury and function, i.e., release of flavin mononucleotide from complex I, perfusate NADH, and mitochondrial CO2 production during HOPE, allowing a more objective interpretation of liver quality on a subcellular level, compared to donor derived data. INTERPRETATION: HOPE after cold storage is a highly suitable and easy to perform perfusion approach, which allows reliable liver graft assessment, enabling surgeons to make a fact based decision on whether or not to implant the organ. HOPE-treatment should be combined with viability assessment particularly when used for high-risk organs, including DCD livers or organs with relevant steatosis. FUNDING: This study was supported by the Swiss National Foundation (SNF) grant 320030_189055/1 to PD.

Defatting of Human Livers During Long-Term e x situ Normothermic Perfusion: Novel Strategy to Rescue Discarded Organs for Transplantation.

OBJECTIVE: To develop a protocol for the defatting of steatotic liver grafts during long-term ex situ normothermic machine perfusion. BACKGROUND: Despite the alarming increase in donor organ shortage, the highly prevalent fatty liver grafts are often discarded due to the risk of primary nonfunction. Effective strategies preventing such outcomes are currently lacking. An exciting new avenue is the introduction of ex situ normothermic machine perfusion (NMP), enabling a liver to remain fully functional for up to 2 weeks and providing a unique window of opportunity for defatting before transplantation. METHODS: Over a 5-year period, 23 discarded liver grafts and 28 partial livers from our resection program were tested during ex situ normothermic machine perfusion. The steatosis degree was determined on serial biopsies by expert pathologists, and triglyceride contents were measured simultaneously. RESULTS: Of 51 liver grafts, 20 were steatotic, with up to 85% macrovesicular steatosis, and were perfused for up to 12 days. Ten livers displayed marked (5 of which almost complete) loss of fat, while the other 10 did not respond to long-term perfusion. Successful defatting was related to prolonged perfusion, automated glucose control, circadian nutrition, and L-carnitine/fenofibrate supplementation. Pseudopeliotic steatosis and the associated activation of Kupffer/stellate cells were unexpected processes that might contribute to defatting. Synthetic and metabolic functions remained preserved for most grafts until perfusion ended. CONCLUSION: Ex situ long-term perfusion effectively reduces steatosis while preserving organ viability and may in the future allow transplantation of primarily unusable high-risk grafts, significantly increasing the number of organs available for transplantation.

Novel Benchmark Values for Open Major Anatomic Liver Resection in Non-cirrhotic Patients: A Multicentric Study of 44 International Expert Centers.

OBJECTIVE: This study aims at establishing benchmark values for best achievable outcomes following open major anatomic hepatectomy for liver tumors of all dignities. BACKGROUND: Outcomes after open major hepatectomies vary widely lacking reference values for comparisons among centers, indications, types of resections, and minimally invasive procedures. METHODS: A standard benchmark methodology was used covering consecutive patients, who underwent open major anatomic hepatectomy from 44 high-volume liver centers from 5 continents over a 5-year period (2016-2020). Benchmark cases were low-risk non-cirrhotic patients without significant comorbidities treated in high-volume centers (≥30 major liver resections/year). Benchmark values were set at the 75th percentile of median values of all centers. Minimum follow-up period was 1 year in each patient. RESULTS: Of 8044 patients, 2908 (36%) qualified as benchmark (low-risk) cases. Benchmark cutoffs for all indications include R0 resection ≥78%; liver failure (grade B/C) ≤10%; bile leak (grade B/C) ≤18%; complications ≥grade 3 and CCI ® ≤46% and ≤9 at 3 months, respectively. Benchmark values differed significantly between malignant and benign conditions so that reference values must be adjusted accordingly. Extended right hepatectomy (H1, 4-8 or H4-8) disclosed a higher cutoff for liver failure, while extended left (H1-5,8 or H2-5,8) were associated with higher cutoffs for bile leaks, but had superior oncologic outcomes, when compared to formal left hepatectomy (H1-4 or H2-4). The minimal follow-up for a conclusive outcome evaluation following open anatomic major resection must be 3 months. CONCLUSION: These new benchmark cutoffs for open major hepatectomy provide a powerful tool to convincingly evaluate other approaches including parenchymal-sparing procedures, laparoscopic/robotic approaches, and alternative treatments, such as ablation therapy, irradiation, or novel chemotherapy regimens.

Normalization of lipid oxidation defects arising from hypoxia early posthepatectomy prevents liver failure in mouse.

Surgical liver failure (SLF) develops when a marginal amount of hepatic mass is left after surgery, such as following excessive resection. SLF is the commonest cause of death due to liver surgery; however, its etiology remains obscure. Using mouse models of standard hepatectomy (sHx) (68%, resulting in full regeneration) or extended hepatectomy (eHx) (86%/91%, causing SLF), we explored the causes of early SLF related to portal hyperafflux. Assessing the levels of HIF2A with or without oxygenating agent inositol trispyrophosphate (ITPP) indicated hypoxia early after eHx. Subsequently, lipid oxidation (PPARA/PGC1α) was downregulated and associated with persisting steatosis. Mild oxidation with low-dose ITPP reduced the levels of HIF2A, restored downstream PPARA/PGC1α expression along with lipid oxidation activities (LOAs), and normalized steatosis and other metabolic or regenerative SLF deficiencies. Promotion of LOA with L-carnitine likewise normalized the SLF phenotype, and both ITPP and L-carnitine markedly raised survival in lethal SLF. In patients who underwent hepatectomy, pronounced increases in serum carnitine levels (reflecting LOA) were associated with better recovery. Lipid oxidation thus provides a link between the hyperafflux of O2-poor portal blood, the metabolic/regenerative deficits, and the increased mortality typifying SLF. Stimulation of lipid oxidation-the prime regenerative energy source-particularly through L-carnitine may offer a safe and feasible way to reduce SLF risks in the clinic.

Robotic Distal Pancreatectomy: A Novel Standard of Care? Benchmark Values for Surgical Outcomes From 16 International Expert Centers.

BACKGROUND AND OBJECTIVE: Robotic distal pancreatectomy (DP) is an emerging attractive approach, but its role compared with laparoscopic or open surgery remains unclear. Benchmark values are novel and objective tools for such comparisons. The aim of this study was to identify benchmark cutoffs for many outcome parameters for DP with or without splenectomy beyond the learning curve. METHODS: This study analyzed outcomes from international expert centers from patients undergoing robotic DP for malignant or benign lesions. After excluding the first 10 cases in each center to reduce the effect of the learning curve, consecutive patients were included from the start of robotic DP up to June 2020. Benchmark patients had no significant comorbidities. Benchmark cutoff values were derived from the 75th or the 25th percentile of the median values of all benchmark centers. Benchmark values were compared with a laparoscopic control group from 4 high-volume centers and published open DP landmark series. RESULTS: Sixteen centers contributed 755 cases, whereof 345 benchmark patients (46%) were included the analysis. Benchmark cutoffs included: operation time ≤300 minutes, conversion rate ≤3%, clinically relevant postoperative pancreatic fistula ≤32%, 3 months major complication rate ≤26.7%, and lymph node retrieval ≥9. The comprehensive complication index at 3 months was ≤8.7 without deterioration thereafter. Compared with robotic DP, laparoscopy had significantly higher conversion rates (5×) and overall complications, while open DP was associated with more blood loss and longer hospital stay. CONCLUSION: This first benchmark study demonstrates that robotic DP provides superior postoperative outcomes compared with laparoscopic and open DP. Robotic DP may be expected to become the approach of choice in minimally invasive DP.

Isolation of Regenerating Hepatocytes after Partial Hepatectomy in Mice.

Partial hepatectomy has been widely used to investigate liver regeneration in mice, but the isolation of high yields of viable hepatocytes for downstream single-cell applications is challenging. A marked accumulation of lipids within regenerating hepatocytes is observed during the first 2 days of normal liver regeneration in mice. This so-called transient regeneration-associated steatosis (TRAS) is temporary but partially overlaps the major proliferative phase. Density-gradient purification is the backbone of most existing protocols for the isolation of primary hepatocytes. As gradient purification relies on the density and size of cells, it separates non-steatotic from steatotic hepatocyte populations. Therefore, fatty hepatocytes often are lost, yielding non-representative hepatocyte fractions. The presented protocol describes an easy and reliable method for the in vivo isolation of regenerating hepatocytes regardless of their lipid content. Hepatocytes from male C57BL/6 mice are isolated 24-48 h after hepatectomy by a classic two-step collagenase perfusion approach. A standard peristaltic pump drives the warmed solutions via the catheterized inferior vena cava into the remnant, using a retrograde perfusion technique with outflow through the portal vein. Hepatocytes are dissociated by collagenase for their release from the Glisson's capsule. After washing and careful centrifugation, the hepatocytes can be used for any downstream analyses. In conclusion, this paper describes a straightforward and reproducible technique for the isolation of a representative population of regenerating hepatocytes after partial hepatectomy in mice. The method may also aid the study of fatty liver disease.

Real-World Experience Treating Pediatric Epilepsy Patients With Cenobamate.

Introduction: In one third of all patients with epilepsy, seizure freedom is not achieved through anti-seizure medication (ASM). These patients have an increased risk of earlier death, poorer cognitive development, and reduced quality of life. Cenobamate (CNB) has recently been approved as a promising novel ASM drug for the treatment of adults with focal-onset epilepsy. However, there is little experience for its application in pediatric patients. Methods: In a multicenter study we evaluated retrospectively the outcome of 16 pediatric patients treated "off label" with CNB. Results: In 16 patients with a mean age of 15.38 years, CNB was started at an age of 15.05 years due to DRE. Prior to initiation of therapy, an average of 10.56 (range 3-20) ASM were prescribed. At initiation, patients were taking 2.63 (range 1-4) ASM. CNB was increased by 0.47 ± 0.27mg/kg/d every 2 weeks with a mean maximum dosage of 3.1 mg/kg/d (range 0.89-7) and total daily dose of 182.81 mg (range 50-400 mg). Seizure freedom was achieved in 31.3% and a significant seizure reduction of >50% in 37.5%. Adverse events occurred in 10 patients with fatigue/somnolence as the most common. CNB is taken with high adherence in all but three patients with a median follow-up of 168.5 days. Conclusion: Cenobamate is an effective ASM for pediatric patients suffering from drug-resistant epilepsy. In addition to excellent seizure reduction or freedom, it is well-tolerated. Cenobamate should be considered as a novel treatment for DRE in pediatric patients.

Liver Transplantation as a New Standard of Care in Patients With Perihilar Cholangiocarcinoma? Results From an International Benchmark Study.

OBJECTIVE: To define benchmark values for liver transplantation (LT) in patients with perihilar cholangiocarcinoma (PHC) enabling unbiased comparisons. BACKGROUND: Transplantation for PHC is used with reluctance in many centers and even contraindicated in several countries. Although benchmark values for LT are available, there is a lack of specific data on LT performed for PHC. METHODS: PHC patients considered for LT after Mayo-like protocol were analyzed in 17 reference centers in 2 continents over the recent 5-year period (2014-2018). The minimum follow-up was 1 year. Benchmark patients were defined as operated at high-volume centers (≥50 overall LT/year) after neoadjuvant chemoradiotherapy, with a tumor diameter <3 cm, negative lymph nodes, and with the absence of relevant comorbidities. Benchmark cutoff values were derived from the 75th to 25th percentiles of the median values of all benchmark centers. RESULTS: One hundred thirty-four consecutive patients underwent LT after completion of the neoadjuvant treatment. Of those, 89.6% qualified as benchmark cases. Benchmark cutoffs were 90-day mortality ≤5.2%; comprehensive complication index at 1 year of ≤33.7; grade ≥3 complication rates ≤66.7%. These values were better than benchmark values for other indications of LT. Five-year disease-free survival was largely superior compared with a matched group of nodal negative patients undergoing curative liver resection (n=106) (62% vs 32%, P <0.001). CONCLUSION: This multicenter benchmark study demonstrates that LT offers excellent outcomes with superior oncological results in early stage PHC patients, even in candidates for surgery. This provocative observation should lead to a change in available therapeutic algorithms for PHC.

Long-term outcomes of transplant kidneys donated after circulatory death.

BACKGROUND: Donation after circulatory death (DCD) represents up to 40% of used kidney grafts. While studies have shown similar outcomes compared with donation after brain death (DBD) in the short term and mid-term, no data on long-term outcomes exist. METHODS: We retrospectively analysed patients transplanted at our institution between January 1985 and March 2000. All DCD recipients were matched one-to-one with patients transplanted with DBD grafts during this period according to sex, age and year of transplantation and followed up until December 2020. During this period, 1133 kidney transplantations were performed, of which 122 were with a DCD graft. RESULTS: The median graft survival after 35 years of follow-up was 23 years [277 months {95% confidence interval (CI) 182-372}] in DBD recipients and 24.5 years [289 months (95% CI 245-333)] in DCD recipients (P = 0.65; hazard ratio 0.91). Delayed graft function occurred in 47 patients in the DCD group compared with 23 in the DBD group (P < 0.001), albeit without a significant long-term outcome difference in graft or patient survival. We could not show any difference in graft function in terms of creatinine levels (133 versus 119 µmol/L), proteinuria (370 versus 240 mg/24 h) and glomerular filtration rate slope (-0.6 versus -0.3 mL/min/year) between the two groups for graft survival >20 years. CONCLUSIONS: This is the first study to show similar graft survival and function in DCD kidneys compared with DBD kidneys after 35 years of follow-up. DCD grafts are a valuable resource and can be utilized in the same way as DBD grafts.

Perihilar Cholangiocarcinoma - Novel Benchmark Values for Surgical and Oncological Outcomes From 24 Expert Centers.

OBJECTIVE: The aim of this study was to define robust benchmark values for the surgical treatment of perihilar cholangiocarcinomas (PHC) to enable unbiased comparisons. BACKGROUND: Despite ongoing efforts, postoperative mortality and morbidity remains high after complex liver surgery for PHC. Benchmark data of best achievable results in surgical PHC treatment are however still lacking. METHODS: This study analyzed consecutive patients undergoing major liver surgery for PHC in 24 high-volume centers in 3 continents over the recent 5-year period (2014-2018) with a minimum follow-up of 1 year in each patient. Benchmark patients were those operated at high-volume centers (≥50 cases during the study period) without the need for vascular reconstruction due to tumor invasion, or the presence of significant co-morbidities such as severe obesity (body mass index ≥35), diabetes, or cardiovascular diseases. Benchmark cutoff values were derived from the 75th or 25th percentile of the median values of all benchmark centers. RESULTS: Seven hundred eight (39%) of a total of 1829 consecutive patients qualified as benchmark cases. Benchmark cut-offs included: R0 resection ≥57%, postoperative liver failure (International Study Group of Liver Surgery): ≤35%; in-hospital and 3-month mortality rates ≤8% and ≤13%, respectively; 3-month grade 3 complications and the CCI: ≤70% and ≤30.5, respectively; bile leak-rate: ≤47% and 5-year overall survival of ≥39.7%. Centers operating mostly on complex cases disclosed better outcome including lower post-operative liver failure rates (4% vs 13%; P = 0.002). Centers from Asia disclosed better outcomes. CONCLUSION: Surgery for PHC remains associated with high morbidity and mortality with now the availability of benchmark values covering 21 outcome parameters, which may serve as key references for comparison in any future analyses of individuals, group of patients or centers.

CD26 as a target against fibrous formation in chronic airway rejection lesions.

AIMS: Chronic lung allograft dysfunction (CLAD) after lung transplantation (Tx) is the clinical result of chronic airway rejection lesions (CARL), histomorphologically described as either obliterative remodeling of small airways or alveolar fibroelastosis, or as a combination of both. We here investigated the CD26-inhibitory effect on CD26-expressing CARL. MAIN METHODS: CARL were induced by BALB/c â†’ C57BL/6 mouse Tx under mild immunosuppression. CARL-related pro-fibrotic mediators were determined by RT-qPCR and western blotting (WB), EMT and ERK markers by WB. CD26 co-expression by immunofluorescence. CD26 was inhibited by Vildagliptin, gene depleted by CD26-/- mice. Primary lung fibroblasts were employed for ex vivo analyses. Samples from lung transplant patients with CLAD were analyzed by immunohistochemistry. KEY FINDINGS: CARL revealed a significantly higher expression of profibrotic proteins vs. normal lungs (p < 0.05). CD26 and EMT co-expressed in CARL with significantly higher Vimentin, Slug, Hif-1α, α-SMA expression vs. normal lungs (p < 0.05). Vildagliptin decreased the expression of α-SMA and N-cadherin in wild type (WT) lung fibroblasts (p < 0.05). Primary lung fibroblasts from WT and CD26-/- mice treated with TGF-ß1, IFN-γ, and FGF showed a reduction of EMT protein expression, proliferation, and reduced activation of ERK in CD26-/- mice vs. WT mice. CD26-positive cells were found in patient samples with CLAD in areas of loose fibrosis, but not in areas of dense fibrosis. SIGNIFICANCE: CD26 is expressed in CARL-developing lung transplants and CD26-inhibition downregulates fibrosis-forming mediators and fibroblast proliferation. CD26 thus qualifies as a target to attenuate the development of CARL mainly via modulation of ERK and the EMT pathway.

Site of Recurrence and Survival After Surgery for Colorectal Peritoneal Metastasis.

BACKGROUND: Multimodal treatment, including systemic treatment and surgery, improved the prognosis of peritoneal metastasis (PM). Despite all efforts, recurrence rates remain high, and little data are available about clinical behavior or molecular patterns of PM in comparison to hematogenous metastasis. Here, we aimed to analyze recurrence patterns after multimodal treatment for PM from colorectal cancer. METHODS: Patients with colorectal PM undergoing multimodal treatment including systemic chemotherapy and cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) between 2005 and 2017 at 4 centers were analyzed retrospectively. RESULTS: A total of 505 patients undergoing CRS/HIPEC were analyzed. Of the patients, 82.1% received preoperative chemotherapy. Median peritoneal cancer index was 6 (interquartile range = 3-11). Median disease-free and overall survival was 12 (95% confidence interval [CI] = 11 to 14) months and 51 (95% CI = 43 to 62) months, respectively. Disease recurred in 361 (71.5%) patients, presenting as isolated peritoneal recurrence in 24.6%, isolated hematogenous recurrence in 28.3%, and mixed recurrence in 13.9% of patients. Recurrence to the peritoneum was associated with an impaired time from recurrence to death of 21 (95% CI = 18 to 31) months for isolated peritoneal and 22 (95% CI = 16 to 30) months for mixed recurrence, compared with 43 (95% CI = 31 to >121) months for hematogenous recurrence (hazard ratio [HR] = 1.79, 95% CI = 1.27 to 2.53; P = .001; and HR = 2.44, 95% CI = 1.61 to 3.79; P < .001). On multiple logistic regression analysis, RAS mutational status (odds ratio [OR] = 2.42, 95% CI = 1.11 to 5.47; P = .03) and positive nodal stage of the primary (OR = 3.88, 95% CI = 1.40 to 11.86; P = .01) were identified as predictive factors for peritoneal recurrence. CONCLUSIONS: This study highlights the heterogeneity of peritoneal metastasis in patients with colorectal cancer. Recurrent peritoneal metastasis after radical treatment represents a more aggressive subset of metastatic colorectal cancer.

Peritoneal Metastasis: Current Status and Treatment Options.

Peritoneal metastasis (PM) originating from gastrointestinal cancer was considered a terminal disease until recently. The advent of better systemic treatment, a better understanding of prognostic factors, and finally, the advent of novel loco-regional therapies, has opened the door for the multimodal treatment of PM. These strategies, including radical surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) showed surprisingly good results, leading to the prolonged survival of patients with peritoneal metastasis. This has triggered a significant body of research, leading to the molecular characterization of PM, which may further help in the development of novel treatments. This review summarizes current evidence on peritoneal metastasis and explores potential novel mechanisms and therapeutic approaches to treat patients with peritoneal metastasis.

Sleep-Disordered Breathing in REM Sleep Behavior Disorder with or without Parkinson's Disease.

REM sleep behavior disorder (RBD) might render patients with Parkinson's disease prone to sleep-disordered breathing. This retrospective polysomonographic study assessed the prevalence of sleep-disordered breathing in 108 consecutive patients with either both Parkinson's disease and RBD (n = 37), Parkinson's disease without RBD (n = 21), or isolated RBD (n = 50). Across all patients, 25% had at least moderate sleep-related breathing disorder, without significant differences between groups. Following multivariable analysis, RBD influenced sleep-related breathing parameters modestly but not significantly, whereas body mass index had a prominent impact. Further studies with larger patient cohorts are needed, and confounders like body mass index must adequately be controlled for.

A syndrome of the dentate nucleus mimicking psychogenic ataxia.

To date, cerebellar involvement in control of non-motor functions like cognition and emotion is increasingly well established. Current models suggest that motor and non-motor networks connecting the cerebellum with cortical areas operate independently in closed and segregated loops. Here, we report a 59-year-old female patient with a small cerebellar lesion that shows that cognitive activation can significantly influence cerebellar motor control. Surprisingly, this led to a clinical picture mimicking a psychogenic disorder. Similar to non-human primates, this case suggests that the human dentate nucleus consists of distinct cognitive and motor domains with additional somatotopical arrangement of the latter. Extending current models of cerebro-cerebellar interaction, this case further illustrates that there can be significant functional cross-talk between motor and cognitive cerebellar networks.