Biology subjects

Krystal, J.

Publications and source records attributed to Krystal, J..

9 recordsLinked to original sources

bioRxiv2025

Beta bursts mediate amygdala gating of hippocampal emotional encoding

The amygdala and hippocampus are key structures in emotional processing, yet the transient neural dynamics coordinating their interaction remain poorly understood. We simultaneously recorded single-neuron activity and local field potentials from these regions in epilepsy patients performing an emotional image-rating task. Neurons in both areas exhibited firing rate changes predictive of subjective emotional valence. While conventional spectral analysis revealed no valence-specific patterns, beta bursts (13-30 Hz)--transient, high-power events-were uniquely modified by task features. In both regions, beta bursts were associated with increased gamma amplitude and enhanced phase coherence, with beta-gamma phase-amplitude coupling capturing emotion-related dynamics. Critically, amygdala beta bursts were associated with strong suppression of hippocampal firing, coinciding with interneuron activation, during negative valence/highest arousal processing, whereas hippocampal bursts showed no reciprocal influence. These findings suggest that beta bursts may represent a temporally precise neural correlate of emotional appraisal and a candidate mechanism for targeted neuromodulation in mood disorders.

neuroscience↗

bioRxiv2025

Opposing Modulation of EEG Aperiodic Component by Ketamine and Thiopental: Implications for the Noninvasive Assessment of Cortical E/I Balance in Humans

The balance between excitatory and inhibitory (E/I) activity is critical for brain function, and its disruption is implicated in neuropsychiatric disorders. Electrophysiological signals can be decomposed into periodic (oscillatory) and aperiodic components. In the power spectrum, the periodic component appears as narrowband peaks, while the aperiodic component underlies its characteristic 1/fx power-law decay. Computational models predict that shifts in E/I balance alter the exponent{chi} in specific directions. In a randomized, double-blind, placebo-controlled, within-subject study, healthy volunteers received subanesthetic doses of ketamine and thiopental during an EEG oddball task. These drugs have opposite effects on E/I balance but comparable sedative profiles. Ketamine reduced the PSD exponent, while thiopental increased it, consistent with computational predictions. Changes in the exponent were associated with subjective and cognitive effects. These findings suggest that the PSD exponent has potential as a noninvasive EEG biomarker sensitive to transient shifts in cortical E/I balance.

neuroscience↗

bioRxiv2022

Ketamine induces multiple individually distinct whole-brain functional connectivity signatures

BackgroundKetamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamines molecular mechanisms connect to its neural and behavioral effects. MethodsWe conducted a double-blind placebo-controlled study in which 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hour). We quantified resting-state functional connectivity via data-driven global brain connectivity, related it to individual ketamine-induced symptom variation, and compared it to cortical gene expression targets. ResultsWe found that: i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; ii) ketamines data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, implicating the role of SST and PVALB interneurons in ketamines acute effects; and iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level. ConclusionsCollectively, these findings support the possibility for developing individually precise pharmacological biomarkers for treatment selection in psychiatry. FundingThis study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1-190420); Swiss Neuromatrix Foundation (Grant No. 2016-0111m Grant No. 2015 - 010); Swiss National Science Foundation under the frame-work of Neuron Cofund (Grant No. 01EW1908), Usona Institute (2015 - 2056).

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bioRxiv2020

A Shift from Value- to Saliency- Neural Encoding of Subjective Value in Combat Veterans with PTSD during Decision Making under Uncertainty

Military personnel engaged in combat are vulnerable to Posttraumatic Stress Disorder (PTSD), following traumatic experiences in the battlefield. Prior research has mostly employed fear-related paradigms to unravel neural underpinnings of fear dysregulation in individuals with PTSD. The ability to acquire and update fear responses depends critically on the individuals ability to cope with uncertainty, yet the role of individual uncertainty attitudes in the development of trauma-related psychopathology has hardly been examined. Here, we investigated the association between PTSD-related alterations and the subjective valuation of uncertain outcomes during decision-making. We used a monetary gambling paradigm inspired by behavioral economics in conjunction with fMRI and explored neural markers of both vulnerability and resilience to PTSD in a group of combat veterans. Behaviorally, PTSD symptom severity was associated with increased aversion to uncertainty. Neurally, activity in the ventromedial prefrontal cortex (vmPFC) during valuation of uncertain options was associated with PTSD symptoms, an effect which was specifically driven by numbing symptoms. Moreover, the neural encoding of the subjective value of those uncertain options was markedly different in the brains of veterans diagnosed with PTSD, compared to veterans who experienced trauma but did not develop PTSD. Most notably, veterans with PTSD exhibited enhanced representations of the saliency of rewards and punishments in the neural valuation system, especially in ventral striatum, compared with trauma-exposed controls. Our results point to a link between the function of the valuation system under uncertainty and the development and maintenance of PTSD symptoms, and stress the significance of studying reward processes in PTSD.

neuroscience↗

bioRxiv2019

Altered White Matter Microstructural Organization in Post-Traumatic Stress Disorder across 3,049 Adults: Results from the PGC-ENIGMA PTSD Consortium

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed, which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3,049 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1,446 individuals with PTSD and 1,603 controls (2152 males/897 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohens d=-0.12, p=0.0021). The tapetum connects the left and right hippocampus, structures for which structure and function have been consistently implicated in PTSD. Results remained significant/similar after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.

neuroscience↗

bioRxiv2018

Rapamycin, an Immunosuppressant and mTORC1 Inhibitor, Triples the antidepressant Response Rate of Ketamine at 2 Weeks Following Treatment: A double-blind, placebo-controlled, cross-over, randomized clinical trial

BACKGROUNDKetamine exerts rapid and robust antidepressant effects thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine.\n\nMETHODSTwenty-three patients suffering a major depressive episode were randomized to oral rapamycin (6 mg) or placebo, each was followed 2 hours later by ketamine 0.5 mg/kg in a double-blind cross-over design with treatment days separated by at least 2 weeks. Depression severity was assessed using Montgomery-[A]sberg Depression Rating Scale (MADRS). Antidepressant response was defined as a MADRS improvement of 50% or more.\n\nRESULTSOver the two-week follow-up, we found a significant treatment by time interaction (F(8,245) = 2.02, p = 0.04), reflecting prolonged antidepressant effects post rapamycin+ketamine treatment. At 2 weeks, we found a significantly higher response rate following rapamycin+ketamine (41%) compared to placebo+ketamine (13%, p = 0.04). However, rapamycin pretreatment did not alter the acute effects of ketamine.\n\nCONCLUSIONUnexpectedly, pretreatment with rapamycin prolonged rather than blocked the acute antidepressant effects of ketamine. This observation raises questions about the role of mTORC1 in the antidepressant effects of keta-mine, raises the possibility that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that limit the duration of ketamine effects. The supplementing of ketamine with rapamycin may be a treat-ment strategy for reducing the frequency of ketamine infusions during maintenance treatment.

neuroscience↗

bioRxiv2018

Reduced Salience and Enhanced Central Executive Connectivity Following PTSD Treatment

BACKGROUNDIn soldiers with posttraumatic stress disorder (PTSD), symptom provocation was found to induce increased connectivity within the salience network, as measured by functional magnetic resonance imaging (fMRI) and global brain connectivity with global signal regression (GBCr). However, it is unknown whether these GBCr disturbances would normalize following effective PTSD treatment.\n\nMETHODS69 US Army soldiers with (n = 42) and without PTSD (n = 27) completed fMRI at rest and during symptom provocation using subject-specific script imagery. Then, participants with PTSD received 6 weeks (12 sessions) of group cognitive processing therapy (CPT) or present-centered therapy (PCT). At week 8, all participants repeated the fMRI scans. The primary analysis used a region-of-interest approach to determine the effect of treatment on salience GBCr. A secondary analysis was conducted to explore the pattern of GBCr alterations posttreatment in PTSD participants compared to controls.\n\nRESULTSOver the treatment period, PCT significantly reduced salience GBCr (p = .02). Compared to controls, salience GBCr was high pretreatment (PCT, p = .01; CPT, p = .03) and normalized post-PCT (p = .53), but not post-CPT (p = .006). Whole-brain secondary analysis found high GBCr within the central executive network in PTSD participants compared to controls. Post hoc exploratory analyses showed significant increases in executive GBCr following CPT treatment (p = .01).\n\nCONCLUSIONThe results support previous models relating CPT to central executive network and enhanced cognitive control while unraveling a previously unknown neurobiological mechanism of PCT treatment, demonstrating treatment-specific reduction in salience connectivity during trauma recollection.

neuroscience↗

bioRxiv2018

Salience Network Disruption in US Army Soldiers with PTSD

BACKGROUNDBetter understanding of the neurobiology of posttraumatic stress disorder (PTSD) may be critical to developing novel, effective therapeutics. Here, we conducted a data-driven investigation using a well-established, graph-based topological measure of nodal strength to determine the extent of functional dysconnectivity in a cohort of active duty US Army soldiers with PTSD compared to controls.\n\nMETHODS102 participants with (n=50) or without PTSD (n=52) completed functional magnetic resonance imaging (fMRI) at rest and during symptom provocation using subject-specific script imagery. Vertex/voxel global brain connectivity with global signal regression (GBCr), a measure of nodal strength, was calculated as the average of its functional connectivity with all other vertices/voxels in the brain gray matter.\n\nRESULTSIn contrast to during resting-state, where there were no group differences, we found a significantly higher GBCr, in PTSD participants compared to controls, in areas within the right hemisphere, including anterior insula, caudal-ventrolateral prefrontal, and rostral-ventrolateral parietal cortices. Overall, these clusters overlapped with the ventral and dorsal salience networks. Post hoc analysis showed increased GBCr in these salience clusters during symptom provocation compared to resting-state. In addition, resting-state GBCr in the salience clusters predicted GBCr during symptom provocation in PTSD participants but not in controls.\n\nCONCLUSIONIn PTSD, increased connectivity within the salience network has been previously hypothesized, based primarily on seed-based connectivity findings. The current results strongly support this hypothesis using whole-brain network measure in a fully data-driven approach. It remains to be seen in future studies whether these identified salience disturbances would normalize following treatment.

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bioRxiv2017

Schizophrenia Exhibits Bi-Directional Brain-Wide Alterations in Cortico-Striato-Cerebellar Circuits

Distributed neural dysconnectivity is considered a hallmark feature of schizophrenia, yet a tension exists between studies pinpointing focal disruptions versus those implicating brain-wide disturbances. The cerebellum and the striatum communicate reciprocally with the thalamus and cortex through monosynaptic and polysynaptic connections, forming cortico-striatal-thalamic-cerebellar (CSTC) functional pathways that may be sensitive to brain-wide dysconnectivity in schizophrenia. It remains unknown if the same pattern of alterations persists across CSTC systems, or if specific alterations exist along key functional elements of these networks. We characterized connectivity along major functional CSTC subdivisions using resting-state functional magnetic resonance imaging in 159 chronic patients and 162 matched controls. Associative CSTC subdivisions revealed consistent brain-wide bi-directional alterations in patients, marked by hyper-connectivity with sensory-motor cortices and hypo-connectivity with association cortex. Focusing on the cerebellar and striatal components, we validate the effects using data-driven k-means clustering of voxel-wise dysconnectivity and support vector machine classifiers. We replicate these results in an independent sample of 202 controls and 145 patients, additionally demonstrating that these neural effects relate to cognitive performance across subjects. Taken together, these results from complementary approaches implicate a consistent motif of brain-wide alterations in CSTC systems in schizophrenia, calling into question accounts of exclusively focal functional disturbances.

neuroscience↗