Photoreceptor loss is the primary cause behind vision impairment and blindness in diseases such as retinitis pigmentosa and age-related macular degeneration. However, the death of rods and cones allows retinoids to permeate the inner retina, causing retinal ganglion cells to become spontaneously hyperactive, severely reducing the signal-to-noise ratio, and creating interference in the communication between the surviving retina and the brain. Treatments aimed at blocking or reducing hyperactivity improve vision initiated from surviving photoreceptors and could enhance the signal fidelity generated by vision restoration methodologies.

Electroencephalography (EEG) has been thoroughly studied for decades in psychiatry research. Yet its integration into clinical practice as a diagnostic/prognostic tool remains unachieved. We hypothesize that a key reason is the underlying patient's heterogeneity, overlooked in psychiatric EEG research relying on a case-control approach. We combine HD-EEG with normative modeling to quantify this heterogeneity using two well-established and extensively investigated EEG characteristics -spectral power and functional connectivity- across a cohort of 1674 patients with attention-deficit/hyperactivity disorder, autism spectrum disorder, learning disorder, or anxiety, and 560 matched controls. Normative models showed that deviations from population norms among patients were highly heterogeneous and frequency-dependent. Deviation spatial overlap across patients did not exceed 40% and 24% for spectral and connectivity, respectively. Considering individual deviations in patients has significantly enhanced comparative analysis, and the identification of patient-specific markers has demonstrated a correlation with clinical assessments, representing a crucial step towards attaining precision psychiatry through EEG.

Proper development of the nervous system depends not only on the inherited DNA sequence, but also on proper regulation of gene expression, as controlled in part by epigenetic mechanisms present in the parental gametes. In this presentation an internationally recognized research advocate explains why researchers concerned about the origins of increasingly prevalent neurodevelopmental disorders such as autism and attention deficit hyperactivity disorder should look beyond genetics in probing the origins of dysregulated transcription of brain-related genes. The culprit for a subset of cases, she contends, may lie in the exposure history of the parents, and thus their germ cells. To illustrate how environmentally informed, nongenetic dysfunction may occur, she focuses on the example of parents' histories of exposure to common agents of modern inhalational anesthesia, a highly toxic exposure that in mammalian models has been seen to induce heritable neurodevelopmental abnormality in offspring born of exposed germline.

Tuberous sclerosis complex (TSC) and focal cortical dysplasia type II (FCDII) are caused by mutations in mTOR pathway genes leading to mTOR hyperactivity, focal malformations of cortical development (fMCD), and seizures in 80-90% of the patients. The current definitive treatments for epilepsy are surgical resection or treatment with everolimus, which inhibits mTOR activity (only approved for TSC). Because both options have severe limitations, there is a major need to better understand the mechanisms leading to seizures to improve life-long epilepsy treatment in TSC and FCDII. To investigate such mechanisms, we recently developed a murine model of fMCD-associated epilepsy that recapitulates the human TSC and FCDII disorders. fMCD are defined by the presence of misplaced, dysmorphic cortical neurons expressing hyperactive mTOR – for simplicity we will refer to these as “mutant” neurons. In our model and in human TSC tissue, we made a surprising finding that mutant neurons express HCN4 channels, which are not normally functionally expressed in cortical neurons, and increased levels of filamin A (FLNA). FLNA is an actin-crossing linking molecule that has also multiple binding partners inside cells. These data led us to ask several important questions: (1) As HCN4 channels are responsible for the pacemaking activity of the heart, can HCN4 channel expression lead to repetitive firing of mutant neurons resulting in seizures? (2) HCN4 is the most cAMP-sensitive of the four HCN isoforms. Does increase in cAMP lead to the firing of mutant neurons? (3) Does increase in FLNA contribute to neuronal alterations and seizures? (4) Is the abnormal HCN4 and FLNA expression in mutant neurons due to mTOR? These questions will be discussed and addressed in the lecture.

The human brain is a heavily interconnected structure giving rise to complex functions. While brain functionality is mostly revealed during wakefulness, the sleeping brain might offer another view into physiological and pathological brain connectivity. Furthermore, there is a large body of evidence supporting that sleep mediates plastic changes in brain connectivity. Although brain plasticity depends on environmental input which is provided in the waking state, disconnection during sleep might be necessary for integrating new into existing information and at the same time restoring brain efficiency. In this talk, I will present structural, molecular, and electrophysiological markers of brain connectivity and sleep-dependent restoration that we have evaluated using Magnetic Resonance Imaging and electroencephalography in a healthy population. In a second step, I will show how we translated the gained findings into two clinical populations in which alterations in brain connectivity have been described, the neuropsychiatric disorder attention-deficit/hyperactivity disorder (ADHD) and the neurologic disorder thalamic ischemic stroke.

Age-related Macular Degeneration (AMD) and Retinitis Pigmentosa (RP) are vision disorders caused by loss of rod and cone photoreceptors, but downstream retinal neurons also show physiological and morphological changes, resulting in the emergence of hyperactivity and rhythmic firing in many retinal ganglion cells (RGC). We recently discovered that retinoic acid (RA) is a key signal that triggers hyperactivity and that blockers of RA unmask light responses in RGCs that would otherwise be obscured. Recent work is revealing where in the retina circuit RA initiates functional changes. Moreover, interfering with the RA signaling pathway with drug or gene therapy can improve spatial vision in a mouse model of RP, providing a new strategy for enhancing low vision in human RP and AMD.