LAUSR

The autonomic nervous system—a term coined by the British physiologist John Newport Langley in 1898—controls the functions of various organs, including the heart, lungs, and intestine, and maintains body homeostasis. Starting with the work of the French physiologist Claude Bernard in the 1860s, research on the functional neuroanatomy of the autonomic nervous system has focused on autonomic circuits at the spinal and brainstem level and at peripheral neurotransmitters. Critical milestones were the discovery of acetylcholine by Otto Loewi and of norepinephrine by Ulf von Euler. More recently, several lines of observational and experimental evidence have suggested that an extensive cortical and subcortical circuitry is involved in the control of the autonomic nervous system, the central autonomic network. Crucial areas of this network include the bilateral insular cortex, anterior cingulate cortex, amygdala, and hypothalamus. The insulae are specialized in polymodal sensory, cognitive, affective, and autonomic integration and therefore regarded as an essential hub of the central autonomic network. Patients with acute ischemic stroke frequently present with cardiac abnormalities, such as a pathological elevation of troponin concentrations, a prolonged QTc interval, and cardiac arrhythmias. The mechanisms leading to cardiac function disorders in patients with stroke, apart from preexisting heart disease, are not well understood. In this issue of Annals of Neurology, Krause and coworkers present a study on the relationship between troponin concentration and lesion location in patients with acute ischemic stroke in the anterior circulation. Their research question was: Are there areas in the brain that, after ischemic infarction, are associated with myocardial injury, as indicated by pathological troponin concentrations? The study excels because of the large number of participants—299 patients with acute ischemic stroke and an initial troponin measurement at admission; 228 of those had a second troponin measurement on average 19 hours later—and the powerful statistical tool used to examine the relationship between structure and function of the brain, voxel-based lesion–symptom mapping. Voxel-based lesion–symptom mapping is an extension of Broca’s seminal lesion method that established the importance of the left inferior frontal gyrus for speech production. Voxel-based lesion–symptom mapping requires the delineation of the lesion on each individual magnetic resonance image and the normalization of individual brains to a standard brain template. Finally, for each voxel, the absolute troponin concentrations at admission and the difference between the first and the second troponin concentration were compared between patients with a lesion of that voxel and patients without a lesion of that voxel. Using this method, Krause et al did not find an association between elevated troponin concentrations at admission and a lesion site anywhere in the anterior circulation. The picture changed when the temporal dynamics of troponin were considered. With the difference between the 2 troponin concentrations as continuous variable, parts of the anterior insular cortex of the right hemisphere, in particular its dorsal subregion, became significant (p< 0.01, corrected for multiple comparisons). The interpretation of this outcome is not as straightforward as the results of most lesion studies using voxel-based lesion–symptom mapping. The traditional lesion study sees a specific lesion location associated with a loss of function. In Krause et al’s study, by contrast, a lesion in the right anterior insular cortex is related to myocardial injury, as indicated by temporal changes in troponin concentration. The authors argue that the right anterior insula is involved in the regulation of parasympathetic tone, citing the results of 2 recent quantitative meta-analyses, and then “suggest that vascular damage to right-sided dorsal anterior insula results in downregulation of parasympathetic activity and thus, in turn, in a relative upregulation of the sympathetic impact on cardiac function.” Additional support for Krause et al’s interpretation comes from a recent case study. For this study, heart rate variability of 2 patients was determined before and during resection of a left and a right insular tumor. The resection of the right insular tumor was