A rapid narrative review of the clinical evolution of psychedelic treatment in clinical trials.

Pre-prohibition psychedelic research with complex psychiatric patients generated a wealth of treatment methodologies and practices, providing invaluable clinical insights pertaining to the medical administration of psychedelics in various mental health diagnoses. Building upon these early studies, which lack the rigor and research tools available today, contemporary psychedelic research has focused on investigating the safety and efficacy of psychedelics in randomized controlled trials via psychometric measures and symptom assessments. Both then and now, the treatment context and the role of clinicians in psychedelic treatment has been recognized as an essential feature for positive patient outcomes. To broaden the knowledge base of modern psychedelic research and support the training of clinicians conducting medically supervised psychedelic research studies, this paper provides a review of pre-prohibition clinical research narratives pertaining to the phenomenology of psychedelic treatment and the role of the non-pharmacological treatment factors in the patient experience. Lastly, this paper explores a range of clinician perspectives and psychological interventions employed in pre-prohibition psychedelic research to inform future research directions and best practice guidelines.

Characteristics of Adolescents with and without a Family History of Substance Use Disorder from a Minority Cohort.

Family history (FH+) of substance use disorder (SUD) is an established risk factor for offspring SUD. The extent to which offspring psychological traits or the family environment, each of which may be relevant to familial transmission of SUD risk, vary by FH+ in socioeconomically disadvantaged populations is less clear. We compared the family/social environmental and psychological characteristics of 73 FH+ and 69 FH- youth ages 12-16, from a study of parental criminal justice system involvement in a primarily low-income, minority urban population. A latent profile analysis (LPA) empirically identified groups of subjects with similar psychological characteristics, which were then compared by FH+. FH+ youths were found to have greater mean household size, greater parental psychological aggression, and a higher mean number of adverse childhood experiences, even without considering parental SUD. FH+ individuals had lower report card grades according to parental report and were more likely to have a history of externalizing disorders than FH- individuals. However, FH+ was not significantly associated with many psychological characteristics or with the class membership from the LPA. In conclusion, among a population of low-income, minority urban youth, FH+ was associated with differences in the family environment and only subtle differences in individual psychological characteristics.

Sex differences in stress responses among underrepresented minority adolescents at risk for substance use disorder.

Adolescence is a period of dramatic physiological changes preparing individuals to face future challenges. Prolonged exposure to stressors during childhood can result in dysregulated stress systems which alter normative physiological progression, leading to exacerbated risk for developing psychiatric disorders. Parental substance use disorder (SUD) is considered a significant childhood stressor which increases risk for the offspring to develop SUD. Thus, it is important to understand stress reactivity among adolescents with parental SUD. We used the Trier Social Stress Task (TSST), which includes a public speech presentation, as an acute stressor. Changes in heart-rate (HR) were measured while disadvantaged minority adolescents with and without a family history (FH+/FH-) of SUD performed the TSST. We investigated sex-specific stress response patterns during the TSST. HR peaked during the speech presentation and was overall higher in females than males. Changes in HR measures between baseline and speech showed an interaction between biological sex and FH group. Specifically, FH- females and FH+ males had significantly larger positive HR changes than FH- males. These results suggest that male and female adolescents with parental SUD have atypical, but divergent changes in stress reactivity that could explain their increased risk for developing SUD via different sexually dimorphic mechanisms.

Changes in appetite during quarantine and their association with pre-COVID-19 mental and physical health.

BACKGROUND: The COVID-19 Pandemic resulted in high levels of fear, anxiety, and stress. People with pre-existing physical and mental health conditions may have been more affected by the sudden changes in daily habits during the initial months of global quarantine imposed during the COVID-19 pandemic. METHODS: We designed the Quarantine, Anxiety, and Diet (QUAD) Survey to investigate the effect of pre-existing health conditions on the relationship of COVID-19 stress and food behavior. The anonymous survey was distributed online and only adults were eligible to participate. RESULTS: The results showed that responders with pre-existing health conditions differed from healthy participants in eating behavior during this time of stress. Compared to those classified as healthy, fewer people with pre-existing physical illness showed an increase in appetite with stress during the COVID-19 pandemic. Responders with pre-existing psychiatric illness were more likely to show increases or decreases in appetite with stress compared to healthy responders. Furthermore, higher BMI was associated with higher rate of increased appetite, whereas low BMI showed a higher rate of decreased appetite, both compared to normal BMI. CONCLUSION: The QUAD Survey demonstrated that individuals with pre-COVID-19 psychiatric conditions are at a higher risk of maladaptive food behavior under stress. Since pre-existing psychiatric illnesses and acute stressors are known risk factors for eating disorders, special attention should be placed on those at risk to mediate the psychological and physical effects of stress and anxiety.

Shapes of subcortical structures in adolescents with and without familial history of substance use disorder.

It has been suggested that intergenerational transmission of risk for substance use disorder (SUD) manifests in the brain anatomy of substance naïve adolescents. While volume and shapes of subcortical structures (SSS) have been shown to be heritable, these structures, especially the pallidum, putamen, nucleus accumbens, and hippocampus, have also been associated with substance use disorders. However, it is not clear if those anatomical differences precede substance use or are the result of that use. Therefore, we examined if volume and SSS of adolescents with a family history (FH+) of SUD differed from adolescents without such a history (FH-). Because risk for SUD is associated with anxiety and impulsivity, we also examined correlations between these psychological characteristics and volume/SSS. Using structural MRI and FSL software, we segmented subcortical structures and obtained indices of SSS and volumes of 64 FH+ and 58 FH- adolescents. We examined group differences in volume and SSS, and the correlations between volume/SSS and trait anxiety and impulsivity. FH+ adolescents had a significant inward deformation in the shape of the right anterior hippocampus compared to FH- adolescents, while the volume of this structure did not differ between groups. Neither shape nor volume of the other subcortical structures differed between groups. In the FH+ adolescents, the left hippocampus shape was positively correlated with both trait anxiety and impulsivity, while in FH- adolescents a negative correlation pattern of SSS was seen in the hippocampus. SSS appears to capture local anatomical features that traditional volumetric analysis does not. The inward shape deformation in the right anterior hippocampus in FH+ adolescents may be related to the known increased risk for behavioral dysregulation leading to SUD in FH+ offspring. Hippocampus shape also exhibits opposite patterns of correlation with anxiety and impulsivity scores across the FH+ and FH- adolescents. These novel findings may reveal neural correlates, not captured by traditional volumetric analysis, of familial transmission of increased vulnerability to SUD.

Ongoing neural oscillations influence behavior and sensory representations by suppressing neuronal excitability.

The ability to process and respond to external input is critical for adaptive behavior. Why, then, do neural and behavioral responses vary across repeated presentations of the same sensory input? Ongoing fluctuations of neuronal excitability are currently hypothesized to underlie the trial-by-trial variability in sensory processing. To test this, we capitalized on intracranial electrophysiology in neurosurgical patients performing an auditory discrimination task with visual cues: specifically, we examined the interaction between prestimulus alpha oscillations, excitability, task performance, and decoded neural stimulus representations. We found that strong prestimulus oscillations in the alpha+ band (i.e., alpha and neighboring frequencies), rather than the aperiodic signal, correlated with a low excitability state, indexed by reduced broadband high-frequency activity. This state was related to slower reaction times and reduced neural stimulus encoding strength. We propose that the alpha+ rhythm modulates excitability, thereby resulting in variability in behavior and sensory representations despite identical input.

Delay discounting and neurocognitive correlates among inner city adolescents with and without family history of substance use disorder.

Adolescents with a family history (FH+) of substance use disorder (SUD) are at a greater risk for SUD, suggested to be partly due to the transmission of behavioral impulsivity. We used a delay discounting task to compare impulsivity in decision-making and its associated brain functioning among FH+ and FH - minority adolescents. Participants chose between Smaller Sooner (SS) and Larger Later (LL) rewards. The SS was available immediately (Now trials) or in the future (Not-Now trials), allowing for greater differentiation between impulsive decisions. The FH+ group showed greater impatience by responding SS more frequently than the FH - group, only on the Now trials, and even when the relative reward differences (RRD) increased. Surprisingly, there were no differences in brain activity between the groups. Combined, the groups showed greater reward activity during the Now vs. Not-Now trials in medial prefrontal/anterior cingulate, posterior cingulate, precuneus, and inferior frontal gyrus (i.e., an immediacy effect). As the RRD increased activation in the reward network decreased, including the striatum, possibly reflecting easy decision-making. These results indicate that risk for SUD, seen behaviorally among FH+ adolescents, may not yet be associated with discernable brain changes, suggesting that early intervention has the potential to reduce this risk.

White matter integrity and functional connectivity in adolescents with a parental history of substance use disorder.

A family history (FH+) of substance use disorder (SUD) increases an adolescent's risk for substance use initiation and progression. Greater impulsivity and reward seeking behavior is known to be associated with such risk. At the neurological level, dysfunction of cortico-striatal and cortico-limbic pathways have been proposed as contributors to the increased SUD risk in adolescents with FH+. In addition, disadvantaged environments have been associated with atypical brain connectivity and higher SUD risk. However, it remains unclear if this increased risk is manifested in structural and functional brain abnormalities prior to regular drug use. To examine this, we employed complementary imaging of structural and functional connectivity of 60 FH+ and 55 FH- minority adolescents, all from families with low socio-economic status. We acquired diffusion tensor-imaging (DTI) and resting state fMRI data across the whole brain. Structural connectivity was examined by measuring fractional anisotropy (FA) using DTI, to indicate integrity of the white matter tracts. Functional connectivity within and between resting state networks was assessed by the correlation of blood-oxygen-level-dependent (BOLD) signal between intra and inter-network nodes. Psychological measures of impulsivity and reward seeking were also obtained with standardized measures, the BIS-11 and the BIS/BAS, and their association with FA and functional connectivity was evaluated. We found no differences in white matter integrity between the groups. Compared to FH-, FH + adolescents showed significantly greater functional connectivity between posterior regions of the Default Mode Network (DMN) and the Fronto-Parietal Network (FPN). While psychological measures of reward seeking behavior did not differ between the FH+ and FH- groups, impulsivity, assessed by the BIS-11, was significantly higher for FH+. However, we did not find significant differences between the FH+ and FH- groups when comparing associations of BIS-11 scores and white matter integrity or functional connectivity measures. The stronger inter-network functional connectivity between the DMN and FPN in FH + adolescents suggests that transmitted risk for SUD may be related to large-scale brain dynamics. The lack of structural differences support the importance of early prevention efforts for FH + adolescents, before initiation of drug use, allowing for healthy brain development.

Parental Occupational Exposure is Associated With Their Children's Psychopathology: A Study of Families of Israeli First Responders.

OBJECTIVE: To examine the association between parental occupational exposure to traumatic events and their children's mental health in families of First Responders (FRs), a neglected area of research. METHODS: In 208 families of Israeli FRs, children's symptoms and comorbidity patterns of seven psychiatric disorders were regressed on parental work-related variables, controlling for relevant covariates. RESULTS: Having a father working as a FR and higher paternal exposure were associated with a greater number of separation anxiety and posttraumatic stress symptoms, respectively. Maternal exposure was associated with a greater number of symptoms of generalized anxiety, panic disorder, depression, and oppositional defiant disorder, and with increased odds of comorbid internalizing symptomatology. CONCLUSIONS: Additional research on children of FRs is encouraged. An adaption to this understudied population of family-centered interventions available for military families could inform targeted prevention efforts.

Orienting and memory to unexpected and/or unfamiliar visual events in children and adults.

For children, new experiences occur very often, and learning to differentiate between old and new events is a fundamental process necessary for appropriate reactions to stimuli. Thus the present study is concerned with maturation of brain responses to repeated novel events. We examined the effect of repetition of familiar (meaningful) and unfamiliar (meaningless) symbols on the event-related-potentials (ERPs) recorded during novelty oddball and recognition memory tasks from children, adolescents and young adults. During the novelty oddball task, repetition of the familiar symbols elicited a reduction in the novelty P3 in the ERPs of all age groups, while repetition of the unfamiliar symbols elicited a reduction in novelty P3 amplitude only in children. As expected, recognition memory performance improved with age and was better for familiar than unfamiliar symbols. For all age groups, ERPs to correctly recognized familiar old symbols elicited a larger positivity than ERPs to correctly identified new symbols, indicating a reliable memory effect. However, ERPs to unfamiliar old and new symbols did not differ in adults and adolescents but did differ in children. The data suggest that children process familiar visual symbols in a similar fashion to that of adults, and that children process unfamiliar symbols differently from adults.

Differences in Seizure Expression Between Magnetic Seizure Therapy and Electroconvulsive Shock.

OBJECTIVE: Evidence suggests that magnetic seizure therapy (MST) results in fewer side effects than electroconvulsive treatment, both in humans treated with electroconvulsive therapy (ECT) as well as in the animal preclinical model that uses electroconvulsive shock (ECS). Evidence suggests that MST results in fewer cognitive side effects than ECT. Although MST offers enhanced control over seizure induction and spread, little is known about how MST and ECT seizures differ. Seizure characteristics are associated with treatment effect. This study presents quantitative analyses of electroencephalogram (EEG) power after electrical and magnetic seizure induction and anesthesia-alone sham in an animal model. The aim was to test whether differential neurophysiological characteristics of the seizures could be identified that support earlier observations that the powers of theta, alpha, and beta but not delta frequency bands were lower after MST when compared with those after ECS. METHODS: In a randomized, sham-controlled trial, 24 macaca mulatte received 6 weeks of daily sessions while scalp EEG was recorded. Electroencephalogram power was quantified within delta, theta, alpha, and beta frequency bands. RESULTS: Magnetic seizure therapy induced lower ictal expression in the theta, alpha and beta frequencies than ECS, but MST and ECS were indistinguishable in the delta band. Magnetic seizure therapy showed less postictal suppression than ECS. Increasing electrical dosage increased ictal power, whereas increasing MST dosage had no effect on EEG expression. CONCLUSIONS: Magnetic seizure therapy seizures have less robust electrophysiological expression than ECS, and these differences are largest in the alpha and beta bands. The relevance of these differences in higher frequency bands to clinical outcomes deserves further exploration. SIGNIFICANCE: Contrasting EEG in ECS and MST may lead to insights on the physiological underpinnings of seizure-induced amnesia and to finding ways to reduce cognitive side effects.

Single pulse TMS differentially modulates reward behavior.

Greater knowledge of cortical brain regions in reward processing may set the stage for using transcranial magnetic stimulation (TMS) as a treatment in patients with avolition, apathy or other drive-related symptoms. This study examined the effects of single pulse (sp) TMS to two reward circuit targets on drive in healthy subjects. Fifteen healthy subjects performed the monetary incentive delay task (MID) while receiving fMRI-guided spTMS to either inferior parietal lobe (IPL) or supplemental motor area (SMA). The study demonstrated decreasing reaction times (RT) for increasing reward. It also showed significant differences in RT modulation for TMS pulses to the IPL versus the SMA. TMS pulses during the delay period produced significantly more RT slowing when targeting the IPL than those to the SMA. This RT slowing carried over into subsequent trials without TMS stimulation, with significantly slower RTs in sessions that had targeted the IPL compared to those targeting SMA. The results of this study suggest that both SMA and IPL are involved in reward processing, with opposite effects on RT in response to TMS stimulation. TMS to these target cortical regions may be useful in modulating reward circuit deficits in psychiatric populations.

Differential heart rate response to magnetic seizure therapy (MST) relative to electroconvulsive therapy: a nonhuman primate model.

Electroconvulsive therapy (ECT) is an effective treatment for severe depression; however, the induced therapeutic seizure acts on the autonomic nervous system and results in significant cardiac effects. This is an important consideration particularly in the elderly. Magnetic seizure therapy (MST) is in development as a less invasive alternative, but its effects on cardiac function have not been studied. We sought to model those effects in nonhuman primates to inform the development of safer neurostimulation interventions. Twenty four rhesus monkeys were randomly assigned to receive 6 weeks of daily treatment with electroconvulsive stimulation (ECS), magnetic seizure therapy (MST) or anesthesia-alone sham. Digitally acquired ECG and an automated R-wave and inter-R interval (IRI) sampling were used to measure intervention effects on heart rate (HR). Significant differences between experimental conditions were found in the HR as evidenced by changes in the immediate post-stimulus, ictal and postictal epochs. Immediate post-stimulus bradycardia was seen with ECS but not with MST. ECS induced significantly more tachycardia than MST or sham in both the ictal and postictal periods. MST resulted in a small, but statistically significant increase in HR during the postictal period relative to baseline. HR was found to increase by 25% and 8% in the ECS and MST conditions, respectively. MST resulted in significantly less marked sympathetic and parasympathetic response than did ECS. This differential physiological response is consistent with MST having a more superficial cortical site of action with less impact on deeper brain structures implicated in cardiac control relative to ECT. The clinical relevance of the topographical seizure spread of MST and its associated effects on the autonomic nervous system remain to be determined in human clinical trials.

Neurophysiological characterization of high-dose magnetic seizure therapy: comparisons with electroconvulsive shock and cognitive outcomes.

Magnetic seizure therapy (MST) is under development as a means of improving cognitive outcomes with convulsive therapy through achieving better control over therapeutic seizure induction than is possible with conventional electroconvulsive therapy. In this investigation, we present the first neurophysiological characterization of high-dose MST (HD-MST, 6x seizure threshold) to see if a higher dose that is often used in human trials retains differential expression relative to electroconvulsive shock (ECS) and to explore the relationship between seizure expression and cognitive outcomes. To this end, rhesus monkeys received 4 weeks of daily treatment with ECS, HD-MST, and anesthesia-alone sham in counterbalanced order, with an interposed recovery period. Two channels of electroencephalogram were recorded during and immediately after the ictal period. Electroencephalogram power within delta, theta, alpha, and beta frequency bands was calculated. Electroconvulsive shock showed significantly more ictal power in all frequency bands than HD-MST (P < 0.01). Electroencephalogram power during the postictal period was significantly different among conditions only for the delta band. Higher ictal expression with ECS was associated with slowed completion time for an orientation task given immediately after the treatments. Our results support earlier findings demonstrating that MST- and ECS-induced seizures elicit differential patterns of ictal expression, consistent with the relatively more superficial stimulation achieved via magnetic induction in comparison with conventional electroconvulsive therapy. These results demonstrate that MST, even at high dose, results in seizures that differ neurophysiologically from ECS. It further suggests that some of the differences in ictal expression may relate to the improved cognitive outcomes seen with MST.

Development of and change in cognitive control: a comparison of children, young adults, and older adults.

Cognitive control involves adjustments in behavior to conflicting information, develops throughout childhood, and declines in aging. Accordingly, developmental and age-related changes in cognitive control and response-conflict detection were assessed in a response-compatibility task. We recorded performance measures, pre-response time (pre-RT) activity and medial frontal negativity (MFN)-sequentially occurring, putative event-related potential (ERP) indexes, respectively, of cognitive control and response-conflict detection. When response conflict reached the highest levels by requiring incompatible responses on posterror trials, children and older adults showed the greatest performance decrements. ERPs indicated that young adults implemented control (pre-RT) and detected the increased conflict (MFN) only when that conflict was at the highest levels, whereas children and older adults did so at lower levels (e.g., posterror, compatible responses). Consequently, the developmental and age-related performance decrements observed here may be due to the undifferentiated and inefficient manner in which children and older adults recruited the processes associated with both cognitive control and response-conflict detection.

Effects of multiple study-test repetition on the neural correlates of recognition memory: ERPs dissociate remembering and knowing.

Event-related potential (ERP) frontal (300-500 ms) and parietal (500-700 ms) episodic memory (EM) effects are thought to reflect, respectively, familiarity and recollection. However, as most ERP studies use preexperimentally familiar items, an alternative idea is that the frontal EM effect reflects conceptual priming. Repetition of unnameable symbols was used to assess modulations of the putative ERP indices of familiarity and recollection. The same symbols were viewed in each of 4 study/test blocks. Increases in familiarity and conceptual processing of symbols did not modulate the frontal EM effect, suggesting that it reflects neither familiarity nor conceptual priming. The magnitude of the parietal EM effect increased and its onset latency decreased across tests for items given remember (R) but not know (K) judgments. R and K old-new topographies differed. These findings support dual-process proposals that familiarity- and recollection-based processes are distinct.

Retrieving object color: the influence of color congruity and test format.

Incongruous episodes, relative to congruous episodes, engender better memory, but it is unclear whether recollection or familiarity is responsible. Hence, objects were encoded in either natural (yellow banana) or unnatural (blue banana) outline colors. Event-related potentials were recorded while memory was assessed by item (IT) and source (ST) tasks. During IT, unnatural color relative to natural color objects produced better memory and more positive parietal activity (500-600 ms) indicative of recollection. Surprisingly, the converse occurred in ST. As the encoding task required a natural/unnatural decision, an unnatural color object would have required activation of its natural counterpart to make an informed decision. Thus, source confusion during ST relative to IT would have led to a recollection disadvantage for unnatural color objects.

Differential neurophysiological effects of magnetic seizure therapy (MST) and electroconvulsive shock (ECS) in non-human primates.

Magnetic seizure therapy (MST) is under development as a means of reducing the side effects of electroconvulsive therapy (ECT) through enhanced control over patterns of seizure induction and spread. We previously reported that chronic treatment with MST resulted in less impairment in cognitive function than electroconvulsive shock (ECS) in a non-human primate model of convulsive therapy. Here we present quantitative analyses of ictal expression and post-ictal suppression following ECS, MST, and anesthesia-alone sham in the same model to test whether differential neurophysiological characteristics of the seizures could be identified. Rhesus monkeys received 4 weeks of daily treatment with ECS, MST, and anesthesia-alone sham in a counterbalanced order separated by a recovery period. Both ECS and MST were given bilaterally at 2.5 x seizure threshold. Neurophysiological characteristics were derived from two scalp EEG electrode recording sites during and immediately following the ictal period, and were compared to sham treatment. EEG power within four frequencies (delta, theta, alpha and beta) was calculated. Our results support earlier findings from intracerebral electrode recordings demonstrating that MST- and ECS- induced seizures elicit differential patterns of EEG activation. Specifically, we found that ECS shows significantly more marked ictal expression, and more intense post-ictal suppression than MST in the theta, alpha, and beta frequency bands (Ps < .05). However, the ECS and MST were indistinguishable in the delta frequency band during both ictal and post-ictal periods. These results demonstrate that magnetic seizure induction can result in seizures that differ in some neurophysiological respects compared with ECS, but that these modalities share some aspects of seizure expression. The clinical significance of these similarities and differences awaits clinical correlation.

The development of control processes supporting source memory discrimination as revealed by event-related potentials.

Improvement in source memory performance throughout childhood is thought to be mediated by the development of executive control. As postretrieval control processes may be better time-locked to the recognition response rather than the retrieval cue, the development of processes underlying source memory was investigated with both stimulus- and response-locked event-related potentials (ERPs). These were recorded in children, adolescents, and adults during a recognition memory exclusion task. Green- and red-outlined pictures were studied, but were tested in black outline. The test requirement was to endorse old items shown in one study color ("targets") and to reject new items along with old items shown in the alternative study color ("nontargets"). Source memory improved with age. All age groups retrieved target and nontarget memories as reflected by reliable parietal episodic memory (EM) effects, a stimulus-locked ERP correlate of recollection. Response-locked ERPs to targets and nontargets diverged in all groups prior to the response, although this occurred at an increasingly earlier time point with age. We suggest these findings reflect the implementation of attentional control mechanisms to enhance target memories and facilitate response selection with the greatest and least success, respectively, in adults and children. In adults only, response-locked ERPs revealed an early-onsetting parietal negativity for nontargets, but not for targets. This was suggested to reflect adults' ability to consistently inhibit prepotent target responses for nontargets. The findings support the notion that the development of source memory relies on the maturation of control processes that serve to enhance accurate selection of task-relevant memories.

Visual novel stimuli in an ERP novelty oddball paradigm: effects of familiarity on repetition and recognition memory.

The orienting response, the brain's reaction to novel and/or out of context familiar events, is reflected by the novelty P3 of the ERP. Contextually novel events also engender high rates of recognition memory. We examined, under incidental and intentional conditions, the effects of visual symbol familiarity on the novelty P3 recorded during an oddball task and on the parietal episodic memory (EM) effect, an index of recollection. Repetition of familiar, but not unfamiliar, symbols elicited a reduction in the novelty P3. Better recognition performance for the familiar symbols was associated with a robust parietal EM effect, which was absent for the unfamiliar symbols in the incidental task. These data demonstrate that processing of novel events depends on expectation and whether stimuli have preexisting representations in long-term semantic memory.