Faculty Bibliography

INTRODUCTION/BACKGROUND:Despite advances in stroke care, readmission rates for patients with ischemic stroke remain high. Although factors such as age, diabetes, and continuous use of antiplatelet agents have been found to predict readmission rates, the impact of after-hospital care has not been examined. METHODS:The present study reviewed the charts of 416 patients with acute ischemic stroke and recorded stroke-related comorbidities, neurology follow-up within 21 days, readmission at 0 to 30 days, readmission at 31 to 90 days, and any reasons for readmission. RESULTS:= .017). Patients with coronary artery disease and diabetes had a significantly higher likelihood of readmission within 0 to 30 days. CONCLUSION/CONCLUSIONS:The present study suggests that neurology follow-up at any point in time for patients with acute ischemic stroke may reduce short-term readmissions, but special attention to optimizing management of other underlying medical conditions, coronary artery disease, or diabetes may also help reduce overall readmissions. Patients with stroke, therefore, may benefit from a follow-up with both the primary care and neurology in a coordinated fashion to prevent early readmissions at 30 days.

BACKGROUND:It is common for patients diagnosed with medial temporal lobe epilepsy (TLE) to have extrahippocampal damage. However, it is unclear whether microstructural extrahippocampal abnormalities are consistent enough to enable classification using diffusion MRI imaging. Therefore, we implemented a support vector machine (SVM)-based method to predict TLE from three different imaging modalities: mean kurtosis (MK), mean diffusivity (MD), and fractional anisotropy (FA). While MD and FA can be calculated from traditional diffusion tensor imaging (DTI), MK requires diffusion kurtosis imaging (DKI). METHODS:Thirty-two TLE patients and 36 healthy controls underwent DKI imaging. To measure predictive capability, a fivefold cross-validation (CV) was repeated for 1000 iterations. An ensemble of SVM models, each with a different regularization value, was trained with the subject images in the training set, and had performance assessed on the test set. The different regularization values were determined using a Bayesian-based method. RESULTS:Mean kurtosis achieved higher accuracy than both FA and MD on every iteration, and had far superior average accuracy: 0.82 (MK), 0.68 (FA), and 0.51 (MD). Finally, the MK voxels with the highest coefficients in the predictive models were distributed within the inferior medial aspect of the temporal lobes. CONCLUSION:These results corroborate our earlier publications which indicated that DKI shows more promise in identifying TLE-associated pathological features than DTI. Also, the locations of the contributory MK voxels were in areas with high fiber crossing and complex fiber anatomy. These traits result in non-Gaussian water diffusion, and hence render DTI less likely to detect abnormalities. If the location of consistent microstructural abnormalities can be better understood, then it may be possible in the future to identify the various phenotypes of TLE. This is important since treatment outcome varies dependent on type of TLE.

Reactive astrogliosis is a response to injury in the central nervous system that plays an essential role in inflammation and tissue repair. It is characterized by hypertrophy of astrocytes, alterations in astrocyte gene expression and astrocyte proliferation. Reactive astrogliosis occurs in multiple neuropathologies, including stroke, traumatic brain injury and Alzheimer's disease, and it has been proposed as a possible source of the changes in diffusion magnetic resonance imaging (dMRI) metrics observed with these diseases. In this study, the sensitivity of dMRI to reactive astrogliosis was tested in an animal model of focal acute and subacute ischemia induced by the vasoconstricting peptide, endothelin-1. Reactive astrogliosis in perilesional cortex was quantified by calculating the astrocyte surface density as determined with a glial fibrillary acidic protein (GFAP) antibody, whereas perilesional diffusion changes were measured in vivo with diffusional kurtosis imaging. We found substantial changes in the surface density of GFAP-positive astrocyte processes and modest changes in dMRI metrics in the perilesional motor cortex following stroke. Although there are time point-specific correlations between dMRI and histological measures, there is no definitive evidence for a causal relationship.

Using a genetic mouse model that faithfully recapitulates a DISC1 genetic alteration strongly associated with schizophrenia and other psychiatric disorders, we examined the impact of this mutation within the prefrontal cortex. Although cortical layering, cytoarchitecture, and proteome were found to be largely unaffected, electrophysiological examination of the mPFC revealed both neuronal hyperexcitability and alterations in short-term synaptic plasticity consistent with enhanced neurotransmitter release. Increased excitability of layer II/III pyramidal neurons was accompanied by consistent reductions in voltage-activated potassium currents near the action potential threshold as well as by enhanced recruitment of inputs arising from superficial layers to layer V. We further observed reductions in both the paired-pulse ratios and the enhanced short-term depression of layer V synapses arising from superficial layers consistent with enhanced neurotransmitter release at these synapses. Recordings from layer II/III pyramidal neurons revealed action potential widening that could account for enhanced neurotransmitter release. Significantly, we found that reduced functional expression of the voltage-dependent potassium channel subunit K_v1.1 substantially contributes to both the excitability and short-term plasticity alterations that we observed. The underlying dysregulation of K_v1.1 expression was attributable to cAMP elevations in the PFC secondary to reduced phosphodiesterase 4 activity present in Disc1 deficiency and was rescued by pharmacological blockade of adenylate cyclase. Our results demonstrate a potentially devastating impact of Disc1 deficiency on neural circuit function, partly due to K_v1.1 dysregulation that leads to a dual dysfunction consisting of enhanced neuronal excitability and altered short-term synaptic plasticity.SIGNIFICANCE STATEMENT Schizophrenia is a profoundly disabling psychiatric illness with a devastating impact not only upon the afflicted but also upon their families and the broader society. Although the underlying causes of schizophrenia remain poorly understood, a growing body of studies has identified and strongly implicated various specific risk genes in schizophrenia pathogenesis. Here, using a genetic mouse model, we explored the impact of one of the most highly penetrant schizophrenia risk genes, DISC1, upon the medial prefrontal cortex, the region believed to be most prominently dysfunctional in schizophrenia. We found substantial derangements in both neuronal excitability and short-term synaptic plasticity-parameters that critically govern neural circuit information processing-suggesting that similar changes may critically, and more broadly, underlie the neural computational dysfunction prototypical of schizophrenia.

Adaptation facilitates neural representation of a wide range of diverse inputs, including reward values. Adaptive value coding typically relies on contextual information either obtained from the environment or retrieved from and maintained in memory. However, it is unknown whether having to retrieve and maintain context information modulates the brain's capacity for value adaptation. To address this issue, we measured hemodynamic responses of the prefrontal cortex (PFC) in two studies on risky decision-making. In each trial, healthy human subjects chose between a risky and a safe alternative; half of the participants had to remember the risky alternatives, whereas for the other half they were presented visually. The value of safe alternatives varied across trials. PFC responses adapted to contextual risk information, with steeper coding of safe alternative value in lower-risk contexts. Importantly, this adaptation depended on working memory load, such that response functions relating PFC activity to safe values were steeper with presented versus remembered risk. An independent second study replicated the findings of the first study and showed that similar slope reductions also arose when memory maintenance demands were increased with a secondary working memory task. Formal model comparison showed that a divisive normalization model fitted effects of both risk context and working memory demands on PFC activity better than alternative models of value adaptation, and revealed that reduced suppression of background activity was the critical parameter impairing normalization with increased memory maintenance demand. Our findings suggest that mnemonic processes can constrain normalization of neural value representations.

It has been reported that cross-frequency interactions may play an important role in local processing within thalamus and neocortex, as well as information transfer between subcortical and cortico-cortical brain regions. Strong commonalities in rhythmic network properties have been observed across recording techniques and task demands, but strong neuroscientific theories to situate such observations within a unified framework with direct relevance to explain neuropathologies remain scarce. Based on a comprehensive review of animal and human literature, we probe and introduce a neurophysiological framework to explain how coordinated cross-frequency and interregional oscillatory cortical dynamics underlie typical and atypical brain activation, and the formation of distributed functional ensembles supporting cortical networks underpinning perception and cognition. We propose that local regional activation by an external stimulus via a sensory pathway entails (1) attenuated alpha (8-14 Hz) and increased theta (4-8 Hz) and gamma (30-50 Hz) oscillatory activity, and (2) increased interactions among theta and gamma rhythms. These local dynamics also mediate the integration of activated neural populations into large-scale functional assemblies through neuronal synchronization. This comprehensive perspective into the animal and human literature indicates a further thinking beyond synchrony and connectivity and the readiness for more hypothesis-driven research and modeling toward unified principles of thalamo-cortical processing. We further introduced such a possible framework: "The ATG switch". We also discussed evidence that alpha-theta-gamma dynamics emerging from thalamocortical interactions may be implicated and disrupted in numerous neurological and neuropsychiatric conditions.