Humans have adapted to widespread changes during the past two million years in both environmental and lifestyle factors but our knowledge of how the human brain differs from those of other species in terms of evolutionary adaptations and unique functionality is still very limited. Comparative genomics studies reveal valuable insight, and help determine variations in genomic sequence that may provide functional information to better understand species-specific adaptations. Recent discoveries (e.g. RNA modifications and editing, circular RNAs and multiple long non-coding RNA encoded functions) demonstrate our emerging knowledge of evolving brain function. One of the main routes to generate human-specific features is trough genomic changes, which are therefore valuable in uncovering genes and pathways contributing to development and function, especially in the brain. We updated the list of high confidence human-specific genomic variants that associate with protein-coding genes and found 845 such regions. These are mostly due to gene duplications, the emergence of novel human genes and sequence and structural alterations. Network analysis of these associated protein-coding genes identifies adaptations to brain, immune and metabolic functions as highly involved. We further show that many of these protein-coding genes may be functionally associated with neural activity and generating the expanded human cortex in dynamic spatial and temporal contexts. Our results are consistent with environmental changes, such as immune challenges and alterations in diet, as well as neural sophistication, as significant contributors to recent human evolution. These new findings present an opportunity to combine newly discovered mechanisms, both genetic and epigenetic, with more established concepts into an improved and inclusive picture to better understand the uniquely evolved human brain.