Multispectral imaging devices incorporating up to 256 different spectral channels have recently become available for various healthcare applications, as e.g. laparoscopy, gastroscopy, dermatology or perfusion imaging for wound analysis. Currently, the use of such devices is limited due to very high investment costs and slow capture times. To compensate these shortcomings, single sensors with spectral masking on the pixel level have been proposed. Hence, adequate spectral reconstruction methods are needed. Within this work, two deep convolutional neural networks (DCNN) architectures for spectral image reconstruction from single sensors are compared with each other. Training of the networks is based on a huge collection of different MSI imagestacks, which have been subsampled, simulating 16-channel single sensors with spectral masking. We define a training, validation and test set (‘HITgoC’) resulting in 351 training (631.128 sub-images), 99 validation (163.272 sub-images) and 51 test images. For the application in the field of neurosurgery an additional testing set of 36 image stacks from the Nimbus data collection is used, depicting MSI brain data during open surgery. Two DCNN architectures were compared to bilinear interpolation (BI) and an intensity difference (ID) algorithm. The DCNNs (ResNet-Shinoda) were trained on HITgoC and consist of a preprocessing step using BI or ID and a refinement part using a ResNet structure. Similarity measures used were PSNR, SSIM and MSE between predicted and reference images. We calculated the similarity measures for HitgoC and Nimbus data and determined differences of the mean similarity measure values achieved with the ResNet-ID and baseline algorithms such as BI algorithm and ResNet-Shinoda. The proposed method achieved better results against BI in SSIM (.0644 vs. .0252), PSNR (15.3 dB vs. 9.1 dB) and 1-MSE*100 (.0855 vs. .0273) and compared to ResNet-Shinoda in SSIM (.0103 vs. .0074), PSNR (3.8 dB vs. 3.6 dB) and 1-MSE*100 (.0075 vs. .0047) for HITgoC/Nimbus. In this study, significantly better results for spectral reconstruction in MSI images of open neurosurgery was achieved using a combination of ID-interpolation and ResNet structure compared to standard methods.