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Neurobiological Correlates of Psilocybin Response in Depression

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Neurobiological Correlates of Psilocybin

Response in Depression
Saleha Qasim, MBBS 1, Zaofashan Zaheer 1, Muhammad Youshay Jawad, MBBS 1, Mujeeb

U. Shad, M.D., M.S.C.S.2,3,4

(1) King Edward Medical University, Lahore, Pakistan

(2) University of Nevada Las Vegas, Nevada.

(3) Touro University Nevada College of Osteopathic Medicine, Las Vegas, Nevada

(4) The Valley Health System, Las Vegas, Nevada

Corresponding author:

Saleha Qasim, MBBS, salehaqasim96@gmail.com

Keywords: Psilocybin, Neurobiological, Predictors, Response, Treatment-Resistant, Depression

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Abstract

Many patients with Major Depressive Disorder (MDD) fail to respond to their

antidepressants, adding time and cost to find the most effective treatment with a negative effect

on clinical and functional outcomes. Due to a delayed antidepressant response from

monoaminergic antidepressants and a growing population of treatment resistant-depression

(TRD), efforts are underway to find more effective, tolerable, and rapidly acting treatments. The

FDA approval of rapidly acting intranasal formulation of a psychedelic drug, esketamine, has

reignited interest in other psychedelic agents, such as psilocybin and 3, 4-

methylenedioxymethamphetamine (MDMA) in the management of various psychiatric disorders.

The resurrection of clinical research with psychedelics has produced promising results in the

management of MDD, post-traumatic stress disorder (PTSD), and substance use disorder. A

single session of psilocybin-assisted therapy providing breakthrough perspectives about life and

a window to optimize psychological interventions is challenging decades-old monoaminergic

antidepressant treatments. Neuroimaging studies provide the best insights into the unique

mechanism of action of psilocybin in healthy and depressed participants. Although neuroimaging

data with psilocybin have been reviewed earlier, more recent studies have provided valuable

insights into the unique neurobiological mechanisms underlying psilocybin response. This

systematic review aims to synthesize the neurobiological basis of brain resetting effects of

psilocybin and identify neuroimaging correlates of psilocybin response in depressed patients.

 3

Introduction

Despite significant pharmacological advances, two-thirds of patients with major

depressive disorder (MDD) do not respond to their antidepressant treatment. Finding the most

effective treatment is often time-consuming due to the relatively early onset of adverse effects

and delayed response and leads to medication nonadherence, poor prognosis, high socio-

economic burden, and loss of productive years(McIntyre, Lee, and Mansur 2015; Gibson et al.

2010). An increasing number of patients with failed interventions and a longer duration of

unremitted depression are among the main reasons for an increased number of patients with

treatment-refractory depression (TRD) (Souery, Papakostas, and Trivedi 2006). Despite well-

recognized improvement in neurovegetative symptoms, the most frequently used class of

antidepressants, selective serotonin reuptake inhibitors, have been associated with various

adverse effects, including cognitive haze and emotional blunting (Goodwin et al. 2017). Herein, it

becomes imperative to develop novel antidepressants that are rapidly effective across treatment-

refractory and treatment naïve populations to achieve pre-morbid functionality and subjective

improvements, such as quality of life. The FDA approval of intranasal esketamine, often labeled

as a psychedelic, has reignited interest in exploring the antidepressant effects of other

psychedelics, such as psilocybin and 3,4- methylenedioxymethamphetamine (MDMA). Although

esketamine is rapidly effective and antisuicidal, it is expensive and requires two-hour post-

treatment monitoring due to the elevated risk for adverse effects (Ochs-Ross et al. 2019). In

addition, patient registration in the risk evaluation and mitigation services (REMS) is needed

before esketamine can be prescribed in a supervised setting (Seligman et al. 2019).

Moreover, ketamine-indued activation of mu-opioid receptors adds a potential risk for

addiction(Heifets et al. 2021; Williams et al. 2019). After a long hiatus, the resurrection of

psychedelic research has produced promising results in managing several other psychiatric

disorders, including obsessive-compulsive disorder, post-traumatic stress disorder, substance

use disorder, and existential depression in terminal medical illnesses (Carhart-Harris and
 4

Goodwin 2017; Chi and Gold 2020; Vargas et al. 2020). In a head-to-head comparison, 57% of

the patients receiving psilocybin-assisted therapy remitted with a faster onset of efficacy than 28%

of those receiving escitalopram, an SSRI, with similar tolerability (Carhart-Harris et al. 2021). More

recently, depressed subjects produced a 75% response and 58% remission for at least 12 months

after being randomized to receive immediate or delayed psilocybin-assisted psychotherapy

(Gukasyan et al. 2022). Psilocybin-assisted psychotherapy recently produced a significantly

better response and a faster onset of efficacy than escitalopram (Daws et al. 2022).

One of the most unexpected findings with psilocybin has been its early and sustained

antidepressant effects with significantly better tolerability than other antidepressants. These

findings have aroused significant interest in conducting neuroimaging studies to understand the

neurobiological basis of the unique actions of psilocybin. Although most neuroimaging studies

have been conducted in healthy volunteers, there are growing data to demystify unique

neurobiological mechanisms underlying psilocybin response. This review provides a synopsis of

neuroimaging findings with psilocybin in patients with MDD comparing results from healthy

volunteers and earlier neuroimaging findings with some monoaminergic antidepressants.

Methods

This review was conducted in accordance with the 2020 Preferred Reporting Items for

Systematic Reviews and Meta-Analyses (PRISMA)(Page et al. 2021b).

Search strategy

All online databases (i.e., MEDLINE(R), Embase Classic + Embase, APA PsycINFO, Ovid

Healthstar, Journal@Ovid Full Text, Cochrane and CINAHL) were systematically searched on

June 3rd, 2022, using the following string: (psilocybin) AND (psychedelics) AND (MRI) OR (fMRI))

OR (PET)) OR (SPECT)) OR (imaging)) OR (neuroimaging)).

Eligibility criteria
 5

The review was primarily aimed at synthesizing the pre-and-post treatment changes in

different functional areas and neural circuits of the brain after patients with MDD were

administered a therapeutic dosage of psychedelics, primarily focusing on psilocybin and

secondarily to find putative neuroimaging biomarkers that can predict and/or inform foregoing

treatment. Hence, the following criteria were formed for the selection of studies following PRISMA

guidelines(Page et al. 2021a):

Population: Adult patients aged 18 years and older with a diagnosis of MDD according to the

Diagnostic and Statistical Manual of Mental Disorders (DSM) IV or 5th edition.

Intervention: A therapeutic dosage of a psychedelic is administered with an intent to treat (ITT)

analysis.

Comparison group(s): Antidepressant, placebo, or none.

Outcomes: Comparison of pre-and-post treatment change in brain functioning and neural circuits

through any neuroimaging modality (i.e., functional magnetic resonance imaging [fMRI] or single-

photon emission computed tomography [SPECT]) and/or comments on imaging biomarkers of

response to psilocybin treatment.

Studies: Any original neuroimaging study, i.e., randomized controlled trials (RCTs) or open-label

studies.

Data extraction and analysis

Database search results were imported into the Covidence platform

(https://www.covidence.org/) for deduplication, screening, and risk of bias assessment. Two

reviewers (MYJ, SQ) independently screened the imported titles and abstracts, then assessed

the remaining full texts for eligibility. Conflicts in judgment were resolved by discussion.

The data points to be extracted were determined a priori and included the following

whenever possible: lead author, study type and duration, dosage and sequence of psilocybin

administration, concomitant psychological intervention, modality of neuroimaging technique,

baseline and post-treatment depression scores on validated psychological tools, whole and in-
 6

network brain functional changes and correlation or association of brain functional changes with

response to psilocybin treatment on any relevant clinical outcome (i.e., decrease in depression,

anxiety or rumination symptomatology). A qualitative synthesis of the extracted data was

undertaken consequently.

Risk of bias assessment

Assessments of methodological quality were independently conducted by two reviewers

(SQ and ZZ) using Cochrane's risk of bias tools15. Conflicts in judgments were resolved by

discussions that produced the consensus judgments reported herein. Since both blinded RCTs

and unblinded open-label trials were included, two distinct tools were applied respectively: 1) the

standard Risk of Bias (RoB) tool for randomized-controlled trials, and 2) the tool for Risk of Bias

in Non-randomized Studies of Interventions (ROBINS-I).

Results

The procedures of study selection are presented in a PRISMA flow chart (Figure 1). Out

of 946 studies identified in the initial search, 391 articles were left after duplicates were removed.

These 391 studies underwent title and abstract screening, of which eight studies were eligible for

full-text analysis. After full-text research, six neuroimaging studies on depressed subjects were

included in the narrative synthesis (Roseman et al. 2018; Carhart-Harris et al. 2017; Mertens et

al. 2020; Doss et al. 2021; Daws et al. 2022). As shown in Table 1, the first four studies were

open-label trials without placebo control with a small sample size ranging from 14 to 24 (Carhart-

Harris et al. 2017; Doss et al. 2021; Roseman et al. 2018; Mertens et al. 2020). However, one of

the two trials in the latest study was a randomized controlled trial (RCT) with 43 subjects (Daws

et al. 2022). All studies used fMRI, with one also utilizing magnetic resonance spectroscopy

(MRS) to assess functional and biochemical changes in brain response to psilocybin, respectively

(Doss et al. 2021). Four studies (Mertens et al. 2020; Roseman et al. 2018; Carhart-Harris et al.

2017; Daws et al. 2022) were conducted in patients with TRD except for the RCT from the latest
 7

study, which was completed in patients with major depression (Daws et al. 2022). Two studies

examined the functional brain changes with psilocybin-assisted supportive psychotherapy

(Mertens et al. 2020; Roseman et al. 2018). Psilocybin therapy produced a significant

antidepressant response in all reviewed studies as assessed with the Quick Inventory for

Depressive Symptoms (QIDS; (Rush et al. 2003) or Hamilton Depression Rating Scale (HDRS)

(Hamilton 1960).

Study characteristics and extracted results are presented in Table 1. Furthermore, the

ROBINS-I tool was applied to assess biases in selected open-label trials. Domain-level results of

these quality appraisals are summarized in Figure 2. One limitation that needs to be mentioned

here is that most of the studies were conducted in a single center and could have introduced any

potential bias not measured by the ROBINS-I tool.

Discussion

Although several neuroimaging studies with psilocybin are available in healthy volunteers,

only a few are available in the depressed population, all of which are open-label and have utilized

blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) (Table 1).

Nevertheless, these psilocybin studies in depressed patients have reported interesting changes

in the abnormal brain functioning reported in depressed patients (Goodman et al. 2021; Hamilton

et al. 2011). One of the most important brain networks affected in major depression is the default

mode network (DMN) (Hamilton et al. 2011), associated with self-referential processing (Andrews-

Hanna, Smallwood, and Spreng 2014). Several studies have reported increased activity in DMN

(Hamilton et al. 2011), which explains excessive self-focus in depressed patients (Lyons and

Carhart-Harris 2018). Increased activity in DMN also dysregulates other higher-order brain

networks, such as the central executive network (CEN) associated with cognitive inflexibility (Kim

et al. 2012) and the salience network (SN) associated with negative perceptions about 'self' and

the future (Turnbull et al. 2020; Kim et al. 2012). As depicted in Table 1, most neuroimaging
 8

findings from the reviewed studies involve changes in activation or functional connectivity within

or between one or more of the specific brain regions in the DMN (ventromedial PFC [vmPFC],

posterior cingulate cortex [PCC], precuneus [PC], and inferior lateral parietal cortex [ilPFC], CEN

(dorsolateral PFC and the lateral posterior parietal cortex) and SN (anterior cingulate cortex

[ACC], amygdala, and parahippocampal gyrus [PHG].

The first study reported a greater decrease in resting-state functional connectivity (RSFC)

in parahippocampal (PH)-prefrontal cortex (PFC) and a greater increase in ventromedial PFC

(vmPFC) - inferior lateral parietal cortex (ilPC) after a single 25 mg oral dose of psilocybin in

responders than the non-responders (Carhart-Harris et al. 2017). Both changes in psilocybin-

induced connectivity predicted antidepressant response at 5-weeks. Increased connectivity in

vmPFC-ilPC reflected increased visuospatial ability to perceive self in the context of environment,

while decrease in PH-PFC connectivity represented prefrontal disinhibition allowing the mystical

experience. Although increased RSFC in anterior cingulate cortex (ACC)-posterior cingulate

cortex (PCC)/precuneus (PC) did not correlate with treatment response, increased connectivity

between the anterior and posterior nodes of DMN may reflect a balance between emotionally

laden self- versus other perspectives, respectively and may help improve rumination and

autobiographical memory in depressed patients. Other fMRI studies in depressed patients also

found a significant relationship between a greater RSFC within the vmPFC and rumination scores

in major depression, suggesting an inability to disengage DMN from self-perspective (Berman et

al. 2011; Hamilton et al. 2015). It is worth mentioning that similar changes in DMN connectivity

results have been reported in depressed subjects who responded to electroconvulsive therapy

(ECT) (Mulders et al. 2016).

Psilocybin-induced connectivity changes are transient and time-dependent, and mood

stabilization has been reported after a post-acute reduction in the DMN integrity with psilocybin

(Carhart-Harris et al. 2017) and other psychedelics, such as LSD (Carhart-Harris et al. 2016) and

ayahuasca (Palhano-Fontes et al. 2015). The acute changes in connectivity are labeled as a brain
 9

"RESET" mechanism as seen with ECT, in which initial disintegration facilitates a later

reintegration and resumption of normal functioning. Of note, a concurrent reduction in BOLD

activity has also been reported with a decrease in RSFC in PCC/PC and mPFC with ayahuasca

(Palhano-Fontes et al. 2015). In addition, the psilocybin-induced decoupling between anterior

medial and posterior medial DMN was replicated in another study during a 5-day mindfulness

retreat associated with altered self-perception and subjective ego dissolution (Smigielski et al.

2019).

The second study in depressed subjects, using an fMRI task for face recognition, reported

a significant correlation between activation in the right amygdala to fearful and happy faces after

a single dose of psilocybin lasting for 3-weeks (Roseman et al. 2018). These findings contrast

with the dampening of amygdala activity in response to negative emotional stimuli with

conventional antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs)

(Carhart-Harris et al. 2017; Daws et al. 2022). These neuroimaging differences between

psilocybin and SSRIs suggest entirely different mechanisms of emotional processing (Daws et al.

2022), where SSRIs reduce emotional responsiveness, resulting in emotional numbness

(Goodwin et al. 2017), while psilocybin desensitizes patients to deal with painful emotions

(Roseman et al. 2018; Carhart-Harris et al. 2018).

However, psilocybin-induced amygdala activation is transient, and mood stabilization

occurs after a reduction in amygdala activation. These findings resemble the acute connectivity

changes reported with psilocybin (Carhart-Harris et al. 2017) and ECT (Mulders et al. 2016; Pang

et al. 2022). Psilocybin-induced brain reset in cerebral blood flow has also been reported in

healthy volunteers (Lewis et al. 2017; Vollenweider et al. 1997). The acute disintegration followed

by reintegration of neural circuits with psilocybin provides a brief but powerful window of

opportunity for cognitive reframing, particularly with concurrent psychological support (Mertens et

al. 2020; Roseman et al. 2018). Post-treatment increases in cerebral blood flow (CBF) in ACC,

mPFC, lateral PFC, and medial temporal cortex have been associated with the hallucinatory ego
 10

disintegration in healthy subjects (Carhart-Harris et al. 2012). Similar brain changes have been

reported during ECT-induced seizures(Pang et al. 2022; Mulders et al. 2016).

The next study utilizing an fMRI face recognition task also reported acute changes in FC

between important nodes of the DMN and amygdala in response to fearful and neutral faces after

a week of psilocybin-assisted therapy (Mertens et al. 2020). The most noticeable findings were a

transient post-treatment reduction in right amygdala connectivity with vmPFC with increased

amygdala connectivity with the visual cortex, including precuneus (Mertens et al. 2020). Although

the antidepressant response was not correlated with a reduction in vmPFC-right amygdala FC,

rumination scores were significantly decreased at one week and three months post-psilocybin

treatment. These findings are consistent with results from earlier studies and support time-

dependent changes behind brain reset with psilocybin therapy.

The next study reviewed study reported an increase in psilocybin-induced cognitive and

neural flexibility (Doss et al. 2021). The neural flexibility was expressed as the dynamic functional

connectivity (dFC) between ACC and posterior cingulate cortex (PCC), a finding replicated from

a previous study (Carhart-Harris et al. 2017). However, none of the neuroimaging models

predicted antidepressant response except the model trained on baseline static functional

connectivity (sFC) at 4-week. In addition, the reversal of the positive correlation between neural

and cognitive flexibility after a week of psilocybin treatment suggests that sustained improvement

in dFC may be counterproductive for cognitive flexibility. In other words, psilocybin therapy

provides a transient window of opportunity for cognitive improvement, which closes after a

sustained increase in dFC between ACC and PCC. This is analogous to psilocybin-induced brain

reset as reflected by disintegration and reintegration of neural circuits to deal with painful negative

emotions. This study also reported a decrease in glutamate and NAA in the ACC, which is

counterintuitive as it reflects decrease in neuronal metabolism or a deficit in white matter integrity.

However, these changes may also reflect a transient brain reset.

 11

The latest psilocybin study in depressed subjects combined an open-label and a double-

blind, randomized controlled trial of orally administered psilocybin in treatment-refractory and non-

treatment-refractory patients, respectively (Daws et al. 2022). The second trial compared two

doses of 25 mg of psilocybin therapy three weeks apart with daily 10-20 mg of escitalopram for

6-weeks. Both trials reported a rapid and durable response, which correlated with a lower strength

of division (or modularity) between the DMN, CEN, and SN, suggesting a global integration in

network activity. These network changes are most probably mediated by the psilocybin-induced

activation of serotonin 2A (5-HT2A) receptors (Vollenweider et al. 1998), most prominently

expressed in the DMN, CEN and SN (Beliveau et al. 2020). In contrast, antidepressant response

with escitalopram was significantly lower than the psilocybin response and did not correlate with

changes in any brain networks (Daws et al. 2022). The lack of selective activation of 5HT2A

receptors with SSRIs is perhaps the main reason escitalopram failed to show psilocybin-like

changes in the brain networks (Preskorn 1994). The findings from the first well-designed RCT

carry more weight than the earlier results to support psilocybin's global integration of important

brain networks dysregulated during the depression, providing an opportunity to utilize a network-

based approach in interpreting neuroimaging findings from earlier studies.

Conclusion

The neuroimaging findings from the reviewed studies have produced promising predictors

of psilocybin response, which are uniquely different from neurobiological changes observed with

conventional antidepressants. Psilocybin and other psychedelics are the only antidepressants

after ECT with a positive correlation between a transient "brain reset" mechanism and

antidepressant response, which can potentially revolutionize depression treatment. Future

research should be conducted in large RCTs to replicate and confirm the results from the reviewed

studies, particularly concerning the global integration of dysregulated brain networks underlying

psilocybin's response. In addition, the unique neurobiological effects of psilocybin justify trans-
 12

diagnostic investigations, even including terminally ill patients and those with pervasive disorders,

such as autism and personality disorders.

 13

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Table 1: Summary of neuroimaging and clinical findings from the reviewed psilocybin studies in patients with major depressive disorder.

SN Reference Study Sample Size Gender Diagnosis Imaging Psilocybin dose Psilocybin- Core Imaging Findings Antidepressant Effects Antidepressant Response Predictors
Design M/F Method Assisted within or between the DMN, CEN, or
Therapy SN

1. Carhart-Harris et al. Open label 19 total; 16 15/4 TRD ASL 10 mg followed by None Significant post-treatment decrease in Significant decrease in depressive DMN: At 5 weeks, antidepressant
2017 with ASL and BOLD fMRI 25mg PO after one total CBF in lHG, lPG, lPT, lSTG, lA, symptoms at 1-week post-treatment response was predicted by increased
15 with BOLD week rSMG, and rPO. and 47% responders at week-5 (mean RSFC between vmPFC-bilateral ilPC
fMRI change =−9.2±5.6, 𝑡 = −6.7, 𝑝 < 0.001)
Increased RSFC between sgACC and SN: Antidepressant response correlated
PCC, and between vmPFC and ilPC with decreased CBF in amygdala and
one day post-treatment. decreased RSFC between PH-PFC at 5
weeks.
.

2. Roseman et al. 2018 Open label 20; 19 14 /6 TRD BOLD fMRI Two doses; 10 mg Psychologic Increased post-treatment BOLD Based on BDI scores, response rate of SN: Right amygdala activation to fearful
clinical trial completed followed by 25mg PO al support responses in the right amygdala for 63.2%; & remission rate of 57.9% at 1- vs. neutral faces predicted clinical
both scans after one week before, fearful (p = .001) and happy faces (p = week. improvements at 1-week but not at
during and .022), with a trend effect for neutral 2 and 5 weeks.
after the faces (p = .066). Only the increased Based on QIDS, response at 1-day was
sessions response to fearful faces survived 68.4%, at 1-week 63.2%, at 3-weeks
Bonferroni correction. 63.2%, at 2-week 57.9% and at 5-week
was 47.3%.
3. Mertens et al. 2020 Open label 20 total 14/6 TRD BOLD fMRI Two doses; 10 mg None Increased FC between the amygdala BDI scores were significantly reduced DMN: The post-treatment change in FC
clinical trial (analysis done followed by 25mg PO and visual areas including precuneus in at one week (mean reduction=22.26, between vmPFC and the OPC correlated
for 19) after one week response to happy and neutral faces, SD=11.37, p<0.001); 63.2% of patients with BDI scores and change from
but not fearful faces. showed a treatment response (50% baseline at week 1.
drop in BDI score) at this time-point,
Post-treatment decrease in increased with 57.9% meeting criteria for SN: Correlation between post-treatment
pretreatment FC between the vmPFC remission (BDI⩽9). antidepressant response and amygdala
and right amygdala in response to FC did not survive Bonferroni correction.
fearful & neutral but not happy faces.

4 Doss et al. 2021 Open label 24 8/16 With high fMRI, MRS Two doses PO 1.6 Supportive Post-treatment increase in cognitive All patients with significant improvement CEN: No correlation between post-
clinical trial MDD scores weeks apart; psychother flexibility at 4 weeks. in 17-item GRID version of HAMD score treatment increase in cognitive flexibility
(≥17 on the 20mg/70kg and apy with at 1 week and 5 weeks. and antidepressant response at 4 weeks.
GRID- 30mg/70kg psilocybin Post-treatment increase in dFC
Hamilton adminsitrati between ACC and PCC was inversely DMN: No model predicted
Depression on correlated with cognitive flexibility, antidepressant response except the
Rating Scale despite greater baseline dFC baseline sFC model predicting response
or GRID- associated with better baseline at 4-week.
HAMD) cognitive flexibility.

Reduced concentration of glutamate

and NAA in the ACC but not
hippocampus at 1 week.

5. Daws et al. 2022 Combined 16 in OLT 12/4 in Patients with fMRI Open label: 10mg & Psilocybin Both trials reported an increase in brain Psilocybin response in both trials was DMN, CEN, and SN:
data from 43 in RCT open Major 25mg 1 week apart. assisted modularity across DMN, CEN and SN rapid, durable, and correlated with A decrease in network modularity
an open with 21 in the label Depressive RCT: therapy after psilocybin therapy decreases in fMRI brain network implying a global increase in network
label & a control group trial, Disorder Psilocybin group: 2 x . modularity, suggesting a global integration correlated with antidepressant
RCT with and 22 in the 29/14 in 25mg 3 weeks apart increase in brain network integration. response at 6-months.
placebo psilocybin RCT plus 6-weeks of daily
and active group placebo or 2 x 1mg 3- RCT showed a significantly better and
control weeks apart faster response with two doses of
Control group: psilocybin than daily doses of
Daily 10-20 mg of escitalopram with no differences in
escitalopram x 6- adverse effects were reported.
weeks
Abbreviations: ASL Arterial spin labeling, BOLD blood-oxygen level-dependent, fMRI functional magnetic resonance imaging, FC functional connectivity, sFC static functional connectivity, dFC dynamic functional connectivity, RSFC resting state functional connectivity, MRS Magnetic Resonance Spectroscopy, lHG
left Heschl’s gyrus, lPG left precentral gyrus, lPT left planum temporale, lSTG left superior temporal gyrus, LA left amygdala, rSMG right supramarginal gyrus, rPO right parietal operculum, sgACC subgenual anterior cingulate cortex, PCC posterior cingulate cortex, vmPFC ventromedial prefrontal cortex, ilPC inferior-
lateral parietal cortex, PH-PFC parahippocampal-prefrontal cortex, DMN default mode network, QIDS-SR16 quick Inventory of Depressive Symptomatology (16-Item), NAA N-acetyl aspartate, GRID-HAMD GRID Hamilton Rating Scale for Depression, BDI Beck’s Depression Inventory, OPC occipital-parietal cortex,
DMN default mode network, CEN central executive network, SN salience network
From: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated
guideline for reporting systematic reviews. BMJ 2021;372:n71. doi: 10.1136/bmj.n71
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