Biology subjects

Moussawi, K.

Publications and source records attributed to Moussawi, K..

4 recordsLinked to original sources

bioRxiv2025

Towards individualized deep brain stimulation: A stereoencephalography-based workflow for unbiased neurostimulation target identification

ObjectivesDeep brain stimulation (DBS) is increasingly being used to treat a variety of neuropsychiatric conditions, many of which exhibit idiosyncratic symptom presentations and neural correlates across individuals. Thus, we have utilized inpatient stereoelectroencephalography (sEEG) to identify personalized therapeutic stimulation sites for chronic implantation of DBS. Informed by our experience, we have developed a statistics-driven framework for stimulation testing to identify therapeutic targets. Materials and MethodsFourteen participants (major depressive disorder = 6, chronic pain = 6, obsessive-compulsive disorder = 2) underwent inpatient testing using sEEG and symptom monitoring to identify personalized stimulation targets for subsequent DBS implantation. We present a structured approach to this sEEG testing, integrating a Stimulation Testing Decision Tree with power analysis and effect size considerations to inform adequately powered results to detect therapeutic stimulation sites with statistical rigor. ResultsEffect sizes (Hedges g) of stimulation-induced symptom score changes ranged from -1.5 to +2.39. The standard deviation of sham trial responses was a strong predictor of stimulation response variability, as confirmed by a leave-one-out cross-validated linear regression (R2 = 0.67, permutation p<0.001). Thus, early sham trial data could be used to estimate the variability of stimulation responses for power analysis calculations. We show that approximately 10 sham trials were needed to robustly estimate sham variability. Power analysis (using a paired-t test) showed that for effect sizes [≥] 1.1, roughly 10 trials should be used per stimulation site for sufficiently powered results. ConclusionsThe presented workflow is adaptable to multiple indications and is specifically designed to overcome key challenges experienced during stimulation site testing. Through incorporating sham trials, effect size calculations, and tolerability testing, the described approach can be used to identify personalized and clinically efficacious stimulation sites.

neuroscience↗

bioRxiv2024

Generalized cue reactivity in dopamine neurons after opioids

Cue reactivity is the maladaptive neurobiological and behavioral response upon exposure to drug cues and is a major driver of relapse. The leading hypothesis is that dopamine release by addictive drugs represents a persistently positive reward prediction error that causes runaway enhancement of dopamine responses to drug cues, leading to their pathological overvaluation compared to non-drug reward alternatives. However, this hypothesis has not been directly tested. Here we developed Pavlovian and operant procedures to measure firing responses, within the same dopamine neurons, to drug versus natural reward cues, which we found to be similarly enhanced compared to cues predicting natural rewards in drug-naive controls. This enhancement was associated with increased behavioral reactivity to the drug cue, suggesting that dopamine release is still critical to cue reactivity, albeit not as previously hypothesized. These results challenge the prevailing hypothesis of cue reactivity, warranting new models of dopaminergic function in drug addiction, and provide critical insights into the neurobiology of cue reactivity with potential implications for relapse prevention.

neuroscience↗

bioRxiv2020

Inhibitory ultrapotent chemogenetics activate dopamine D1 receptor-expressing medium spiny neurons

Ultrapotent chemogenetics, including the chloride-permeable inhibitory PSAM4-GlyR receptor, were recently proposed as a powerful strategy to selectively control neuronal activity in awake, behaving animals. We aimed to validate the inhibitory function of PSAM4-GlyR in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) in the ventral striatum. Activation of PSAM4-GlyR with the uPSEM792 ligand enhanced rather than suppressed the activity of D1-MSNs in vivo as indicated by increased c-fos expression in D1-MSNs. Whole-cell recordings in mouse brain slices showed that activation of PSAM4-GlyR did not inhibit firing of action potentials in D1-MSNs. Activation of PSAM4-GlyR depolarized D1-MSNs, attenuated GABAergic inhibition, and shifted the reversal potential of PSAM4-GlyR current to more depolarized potentials, perpetuating the depolarizing effect of receptor activation. The data show that inhibitory PSAM4-GlyR chemogenetics may actually activate certain cell types, and highlight the pitfalls of utilizing chloride conductances to inhibit neurons.

neuroscience↗

bioRxiv2019

Delta glutamate receptor conductance drives excitation of dorsal raphe neurons

The delta glutamate receptors, GluD1R and GluD2R, are mysterious members of the ionotropic glutamate receptor family in that they are not gated by glutamate1,2. One theory is that they are scaffolding proteins or synaptic organizers strictly, rather than ion conducting channels. Although mutant forms and wild type channels have been reported to conduct3,4,5, conduction, gating, and biophysical properties of native GluD1R remain unexplored. Here we show that the inward current induced by activation of 1-adrenergic receptors (1-ARs) in the dorsal raphe nucleus (DR) is mediated by GluD1R. Native GluD1R channels are functional ion channels that are constitutively active under basal conditions and 1-ARs increase the tonic current. This inward current is responsible for the 1-AR-dependent induction of persistent pacemaker-type firing of neurons in the DR. Given the extensive distribution of these receptors, the ionotropic nature of GluDR is proposed to be widespread in the nervous system.

neuroscience↗