Pre-clinical indications of brain stimulation treatments for non-affective psychiatric disorders, a status update.

Over the past two decades noninvasive brain stimulation (NIBS) techniques have emerged as powerful therapeutic options for a range of psychiatric and neurological disorders. NIBS are hypothesized to rebalance pathological brain networks thus reducing symptoms and improving functioning. This development has been fueled by controlled studies with increasing size and rigor aiming to characterize how treatments induce clinically effective change. Clinical trials of NIBS for specific indications have resulted in federal approval for unipolar depression, bipolar depression, smoking cessation, and obsessive-compulsive disorder in the United States, and several other indications worldwide. As a rapidly emerging field, there are numerous pre-clinical indications currently in development using a variety of electrical and magnetic, non-convulsive, and convulsive approaches. This review discusses the state-of-the-science surrounding promising avenues of NIBS currently in pre-approval stages for non-affective psychiatric disorders. We consider emerging therapies for psychosis, anxiety disorders, obsessive-compulsive disorder, and borderline personality disorder, utilizing transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), and magnetic seizure therapy (MST), with an additional brief section for early-stage techniques including transcranial focused ultrasound stimulation (tFUS) and transcranial alternating current stimulation (tACS). As revealed in this review, there is considerable promise across all four psychiatric indications with different NIBS approaches. Positive findings are notable for the treatment of psychosis using tDCS, MST, and rTMS. While rTMS is already FDA approved for the treatment of obsessive-compulsive disorder, methodologies such as tDCS also demonstrate potential in this condition. Emerging techniques show promise for treating non-affective disorders likely leading to future regulatory approvals.

Predictive Biomarkers of Treatment Response in Major Depressive Disorder.

Major depressive disorder (MDD) is a highly prevalent, debilitating disorder with a high rate of treatment resistance. One strategy to improve treatment outcomes is to identify patient-specific, pre-intervention factors that can predict treatment success. Neurophysiological measures such as electroencephalography (EEG), which measures the brain's electrical activity from sensors on the scalp, offer one promising approach for predicting treatment response for psychiatric illnesses, including MDD. In this study, a secondary data analysis was conducted on the publicly available Two Decades Brainclinics Research Archive for Insights in Neurophysiology (TDBRAIN) database. Logistic regression modeling was used to predict treatment response, defined as at least a 50% improvement on the Beck's Depression Inventory, in 119 MDD patients receiving repetitive transcranial magnetic stimulation (rTMS). The results show that both age and baseline symptom severity were significant predictors of rTMS treatment response, with older individuals and more severe depression scores associated with decreased odds of a positive treatment response. EEG measures contributed predictive power to these models; however, these improvements in outcome predictability only trended towards statistical significance. These findings provide confirmation of previous demographic and clinical predictors, while pointing to EEG metrics that may provide predictive information in future studies.

Neurobehavioral measures of coincidence anticipation timing.

Coincidence anticipation (CA) refers to the ability to coordinate responses to the arrival of a moving object. This study investigates the neurobehavioral processes that underlie CA through the measurement of electroencephalography (EEG) recorded during a CA task on a 17-foot plastic rail with evenly spaced LED lights. Participants responded at the anticipated moment a sequence of successively lit LEDs coincided with a stationary target. Healthy young adult participants (Mage = 21) performed six blocks with movement at 20, 30, or 40 mph and the direction either inbound or outbound relative to the participant. Behavioral results demonstrated a main effect of speed and an interaction between speed and direction, with outbound motion producing early responses and inbound motion producing delayed responses that increased at greater speeds. EEG demonstrated characteristic P1, N2, and P3-like visual evoked potentials (VEPs). VEP amplitudes revealed a significant direction by channel interaction for the P1, indicative of more medial responses for inbound motion. Significant laterality differences were present in the N2, whereas the P3 component produced significant main effects and interactions of speed and direction. This novel combination of three-dimensional CA with EEG demonstrates systematic brain responses that are tuned for motion speed and sensitive to different egocentric motion patterns thereby shedding new light on the mechanism of human visual-motor control.

MicroPET evidence for a hypersensitive neuroinflammatory profile of gp120 mouse model of HIV.

Despite increased survivability for people living with HIV (PLWH), HIV-related cognitive deficits persist. Determining biological mechanism(s) underlying abnormalities is critical to minimize the long-term impact of HIV. Positron emission tomography (PET) studies reveal that PLWH exhibit elevated neuroinflammation, potentially contributing to these problems. PLWH are hypersensitive to environmental insults that drive elevated inflammatory profiles. Gp120 is an envelope glycoprotein exposed on the surface of the HIV envelope which enables HIV entry into a cell contributing to HIV-related neurotoxicity. In vivo evidence for mice overexpressing gp120 (transgenic) mice exhibiting neuroinflammation remains unclear. Here, we conducted microPET imaging in gp120 transgenic and wildtype mice, using the radiotracer [(18)F]FEPPA (binds to the translocator protein expressed by activated microglial serving as a neuroinflammatory marker). Imaging was performed at baseline and 24 h after lipopolysaccharide (LPS; 5 mg/kg) treatment (endotoxin that triggers an immune response). Gp120 transgenic mice exhibited elevated [(18F)]FEPPA in response to LPS vs. wildtype mice throughout the brain including dorsal and ventral striata, hypothalamus, and hippocampus. Gp120 transgenic mice are hypersensitive to environmental inflammatory insults, consistent with PLWH, measurable in vivo. It remains to-be-determined whether this heightened sensitivity is connected to the behavioral abnormalities of these mice or sensitive to any treatments.

PET Imaging of Phosphodiesterase-4 Identifies Affected Dysplastic Bone in McCune-Albright Syndrome, a Genetic Mosaic Disorder.

McCune-Albright syndrome (MAS) is a mosaic disorder arising from gain-of-function mutations in the GNAS gene, which encodes the 3',5'-cyclic adenosine monophosphate (cAMP) pathway-associated G-protein, Gsα. Clinical manifestations of MAS in a given individual, including fibrous dysplasia, are determined by the timing and location of the GNAS mutation during embryogenesis, the tissues involved, and the role of Gsα in the affected tissues. The Gsα mutation results in dysregulation of the cAMP signaling cascade, leading to upregulation of phosphodiesterase type 4 (PDE4), which catalyzes the hydrolysis of cAMP. Increased cAMP levels have been found in vitro in both animal models of fibrous dysplasia and in cultured cells from individuals with MAS but not in humans with fibrous dysplasia. PET imaging of PDE4 with 11C-(R)-rolipram has been used successfully to study the in vivo activity of the cAMP cascade. To date, it remains unknown whether fibrous dysplasia and other symptoms of MAS, including neuropsychiatric impairments, are associated with increased PDE4 activity in humans. Methods:11C-(R)-rolipram whole-body and brain PET scans were performed on 6 individuals with MAS (3 for brain scans and 6 for whole-body scans) and 9 healthy controls (7 for brain scans and 6 for whole-body scans). Results:11C-(R)-rolipram binding correlated with known locations of fibrous dysplasia in the periphery of individuals with MAS; no uptake was observed in the bones of healthy controls. In peripheral organs and the brain, no difference in 11C-(R)-rolipram uptake was noted between participants with MAS and healthy controls. Conclusion: This study is the first to find evidence for increased cAMP activity in areas of fibrous dysplasia in vivo. No differences in brain uptake between MAS participants and controls were detected-a finding that could be due to several reasons, including the limited anatomic resolution of PET. Nevertheless, the results confirm the usefulness of PET scans with 11C-(R)-rolipram to indirectly measure increased cAMP pathway activation in human disease.