The role of aripiprazole in modulating putamen and thalamus functional connectivity in early psychosis patients

Abstract

Background:

Early psychosis is marked by cortico-striatal and thalamocortical dysconnectivity, yet how aripiprazole modulates these circuits remains unclear.

Methods:

We examined putamen and thalamus functional connectivity (FC) in 30 early psychosis patients (ultra-high-risk, first-episode psychosis, schizophreniform disorder, or first-episode schizophrenia) and 30 matched healthy controls. At baseline, patients were naïve to dopamine receptor-targeting medication or minimally exposed (<12 weeks). All patients received flexible-dose aripiprazole, and symptoms were assessed using the Positive and Negative Syndrome Scale at baseline, days 14 and 28. Baseline resting-state functional MRI was acquired for patients and controls, and follow-up scans for patients after 41.6 ± 13.9 days of treatment.

Results:

Compared with controls, patients showed hypoconnectivity within/between bilateral putamen, between putamen and thalamus, and between thalamus and salience network (SN) nodes. In contrast, hyperconnectivity was observed between the putamen and both sensorimotor (SM) and default mode network (DMN) nodes, as well as between the thalamus and SM nodes. After treatment with aripiprazole, FC increased within/between bilateral putamen, between putamen and SN nodes, and between thalamus and SN nodes, and decreased between thalamus and SM nodes and between putamen and SM nodes. At the uncorrected level (p < 0.05), increases in FC between the right ventral rostral putamen and bilateral putamen correlated with improvement in positive symptoms.

Conclusion:

Findings suggest aripiprazole partially normalizes aberrant striatal–thalamic coupling early in psychosis, and putaminal FC changes may relate to clinical response. Aripiprazole may achieve therapeutic benefits by restoring integration within striatal hubs and their crosstalk with large-scale networks implicated in psychotic symptom expression.

Keywords

early psychosis aripiprazole putamen thalamus functional connectivity resting-state functional MRI

Introduction

Schizophrenia involves widespread structural, functional, and neurochemical alterations across various brain regions (Birur et al., 2017; Li et al., 2019a). Previous studies using resting-state fMRI (rs-fMRI) have identified changes in regions such as the basal ganglia (including the putamen, caudate nucleus, and globus pallidus), the thalamocortical pathway, and several key neural networks, such as the default mode network (DMN) and salience network (SN) (Dabiri et al., 2022). Task-based fMRI studies have also reported a general pattern of decreased basal ganglia recruitment in schizophrenia (Bernard et al., 2017). However, the use of dopamine receptor-targeting medications and the chronicity of schizophrenia can influence structural or functional neuroimaging findings (Dabiri et al., 2022; Dietsche et al., 2017; Gong et al., 2020; Huhtaniska et al., 2017). Studies focusing on patients naïve to dopamine receptor-targeting medication at the early stage of psychosis are crucial for distinguishing these effects and therefore hold irreplaceable importance in improving our understanding regarding the pathogenesis of schizophrenia. Functional brain imaging studies have identified abnormalities in intrinsic brain activity within the frontal, parietal, occipital cortices, and the striatum in patients with first-episode schizophrenia (FES; Gong et al., 2020).

Disrupted thalamocortical functional connectivity (FC), including reduced prefrontal cortex and increased sensorimotor (SM) cortex connectivity, has been reported consistently in schizophrenia patients (Anticevic et al., 2014; Chen et al., 2020; Ferri et al., 2018; Woodward et al., 2012; Woodward and Heckers, 2016). The thalamic dysconnectivity was also evident in individuals at ultra-high risk (UHR) stage for psychosis (Anticevic et al., 2015; Fryer et al., 2022) and more prominently in those who later converted to psychosis (Anticevic et al., 2015).

The striatum, particularly its dorsal regions which consist of the caudate nucleus and the putamen, plays a critical role in the pathophysiology of schizophrenia (McCutcheon et al., 2019). The striatum is involved in assigning salience to environmental stimuli, processing reward-related signals, and coordinating cortical executive functions, which correspond to positive symptoms, negative symptoms, and cognitive impairments in schizophrenia, respectively (McCutcheon et al., 2019). Previous studies have identified subcortical dopamine dysfunction in the striatum, including the putamen, in both early psychosis and schizophrenia (Kesby et al., 2018). As a key subcortical node of the striatum, the putamen is characterized by high levels of dopaminergic activity (Larsen et al., 2020) and rich in dopamine D2 receptors, which are the primary target of contemporary pharmacological treatments for schizophrenia (Antonini and Leenders, 1993). Aripiprazole is a dopamine-serotonin receptor partial agonist, with clinically relevant activity at dopamine D2 and serotonin 5-HT1A receptors, and is widely used in the treatment of schizophrenia spectrum disorders (Di Sciascio and Riva, 2015). Recent reviews have suggested that third-generation antipsychotics may provide efficacy comparable to earlier agents while showing a more favorable extrapyramidal side-effect profile and possible cognitive advantages in FES (Ricci et al., 2025). Previous studies have demonstrated that aripiprazole occupancy in the striatum is associated with improvements in psychotic symptoms and cognitive function (Kegeles et al., 2008; Shin et al., 2018), highlighting the critical role of the striatum in the pharmacological treatment of schizophrenia.

Treatment with dopamine receptor-targeting medications has been shown to change FC between striatum, thalamus, and other brain regions and the change of FC related to the symptom improvement in FES patients (Feng et al., 2024; Han et al., 2020; Hu et al., 2024; Lui et al., 2010; Sarpal et al., 2015; Zong et al., 2023) and in patients of first-episode psychosis (FEP; Chopra et al., 2021a; Zhang et al., 2023). For patients at UHR stage, there is still no study demonstrating if treatment with dopamine receptor-targeting medications changes FC between striatum, thalamus, and other brain regions.

In this study, we investigated the amplitude of low-frequency fluctuation (ALFF), local coherence (LCOR), and FC between the subregions of putamen, thalamus, and other brain regions in early psychosis patients, most of whom were UHR and FEP, at baseline and after about 6-week aripiprazole treatment. We hypothesized that brain regions associated with the pathophysiology of psychosis, such as the putamen and thalamus, would exhibit abnormal FC at baseline compared to healthy controls (HCs) and some abnormalities would be normalized following aripiprazole treatment. Additionally, we hypothesized that the change of FC following treatment would be associated with the improvement in clinical symptoms.

Materials and methods

Participants

Patient and HC data were drawn from the cohort described in Liu et al. (2013) and Hwang et al. (2022). Thirty patients, aged between 17 and 45 years, were recruited from the outpatient clinics of the Department of Psychiatry in National Taiwan University Hospital (NTUH), along with thirty age- and sex-matched HCs. At baseline, patients were either naïve to dopamine receptor-targeting medication (n = 18) or had received treatment with dopamine receptor-targeting medication for less than 12 weeks before recruitment (short-exposure group, n = 12). The participants met the diagnostic criteria for UHR (n = 14), FEP (n = 11), schizophreniform disorder (n = 3), or FES (n = 2). These groups were examined within a common early psychosis framework because they were all recruited near illness onset under the same aripiprazole treatment protocol and shared limited prior exposure to dopamine receptor-targeting medication, an approach consistent with our previous early psychosis cohort study (Liu et al., 2022). Patients with FES or schizophreniform disorder had experienced their first episode of full-blown psychosis within the past year, meeting the DSM-IV criteria for schizophrenia or schizophreniform disorder, respectively. Patients with FEP had experienced their first episode of full-blown psychosis lasting less than 4 weeks at recruitment. Patients with UHR had subthreshold psychotic symptoms that met the description of attenuated psychotic symptoms or brief limited intermittent psychotic symptoms (McGorry et al., 2003). Both UHR and FEP patients underwent interviews using a Thought/Perception Diagnostic Interview Schedule, including 19 items from the Scale of Prodromal Symptoms (Miller et al., 1999), for a comprehensive assessment of at-risk mental status. All patients received flexible-dose aripiprazole treatment according to the clinical study protocol described previously (Liu et al., 2013). Aripiprazole was initiated at 3.75 mg/day to assess tolerability, increased to 7.5 mg/day during the first 2 weeks if tolerated, and titrated toward 15 mg/day by Week 4 based on clinical response and tolerability. In patients with short prior exposure to dopamine receptor-targeting medication, baseline assessments and aripiprazole initiation were performed after at least 1 week free from such medication. Changes in their symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) at days 14 and 28. Follow-up fMRI scans were obtained after short-term treatment, with a mean interval of 41.6 ± 13.9 days from baseline, depending on participant availability and study scheduling. Patients with a history of mood episodes, current use of psychoactive substances (except for nicotine), neurological diseases, traumatic brain injury, IQ below 70, pregnancy, and those who had received treatment with dopamine receptor-targeting medications for more than 12 weeks were excluded from the study. Healthy subjects underwent a semi-structured diagnostic interview using the Chinese version of the Diagnostic Interview for Genetic Studies (DIGS; Chen et al., 1998) to ensure that they did not have a current or lifetime diagnosis of any psychiatric disorder. Participants with major medical or neurological conditions and comorbid substance abuse (except for nicotine) were excluded based on self-report. All participants provided written informed consent for participation in the study, which was approved by the research ethics committee of NTUH.

Image acquisition and FC preprocessing

MRI data were acquired on a 3-T Siemens TIM Trio (Siemens Healthineers, Forchheim, Germany) with a 32-channel head coil, including high-resolution T1-weighted MPRAGE at 1-mm isotropic and resting-state EPI BOLD runs of about 6 minutes with TR 200 ms, TE 24 ms, 3-mm slices, and eyes closed. Preprocessing with CONN v22a in SPM12 followed the default pipeline with realignment, slice timing correction, ART outlier detection, tissue segmentation, MNI152 normalization, 6-mm FWHM smoothing, Friston 24-parameter motion regression, aCompCor for white matter and CSF, identification of scans with motion over 2 mm or global signal over 3 SD, linear detrending, and a 0.009–0.08 Hz band-pass filter. Full acquisition and preprocessing details are provided in Supplemental Methods.

FC analysis

The FC analysis included the assessment of the ALFF, LCOR, and seed-based connectivity (SBC) analysis. The ALFF values were derived from the variability of low-frequency BOLD signals at each voxel in the brain. This process involved extracting power spectra using fast Fourier transform and subsequently calculating the root mean square of the BOLD signal (Yang et al., 2007). LCOR was computed to assess LCOR at each voxel, defined as the average of correlation coefficients between each voxel and its neighboring voxels, weighted by an isotropic Gaussian kernel (8-mm full-width at half maximum), following the Integrated Local Correlation approach (Deshpande et al., 2009; Nieto-Castanon, 2020). In the SBC analysis, seeds were selected based on a previous study (Di Martino et al., 2008), including the bilateral dorsal caudal putamen (DCP; x = ±28, y = 1, z = 3), dorsal rostral putamen (DRP; x = ±25, y = 8, z = 6), and ventral rostral putamen (VRP; x = ±20, y = 12, z = −3). The bilateral thalamus seeds were defined using the automated anatomical labeling atlas version 3 (AAL-3) (Rolls et al., 2020). Seed-to-voxel connectivity maps were constructed separately for each seed in each subject, and the correlation values were transformed into z-scores using Fisher’s transformation. Group-level analyses of putamen- and thalamus-related FC maps were performed using independent t-tests to compare early psychosis patients and HCs at baseline, and paired t-tests to assess treatment-related FC changes in early psychosis patients between baseline and follow-up. The statistical threshold was set at p < 0.001 (uncorrected) at the voxel level. Significant clusters were identified using a cluster-level false discovery rate (FDR) correction at p < 0.05.

Correlation with symptom severity

PANSS scores were analyzed according to the 5-factor model proposed by Marder et al. (1997), including Delusion/Hallucination, Negative, Disorganized Thought, Uncontrolled Hostility/Excitement, and Anxiety/Depression dimensions (Marder et al., 1997). To examine associations between functional alterations and clinical symptoms, mean ALFF, LCOR, and FC values were extracted from ROIs identified in the baseline and group comparison analyses (patients follow-up vs baseline). These correlation analyses were conducted to explore potential associations between imaging measures and clinical symptoms. Correlation analyses were then conducted between these regional values and PANSS factor scores in the patient group only, using Jamovi (version 2.4.11, The jamovi project, Sydney, Australia). To control for multiple comparisons, p-values were adjusted using the Benjamini–Hochberg FDR procedure separately for each imaging modality. As the ROIs were defined based on group-level effects within the same dataset, these analyses were treated as exploratory.

Results

Sample characteristics and response to aripiprazole treatment

Demographic data and PANSS score results are presented in Table 1. There were no significant differences in age and educational level between early psychosis patients and HCs. The mean duration of illness of patients was 161 days (161.1 ± 218.7). Significant improvements were observed in the PANSS scores, including the total score and each symptom dimension (delusion/hallucination, negative, disorganized, uncontrolled hostility and excitement, anxiety/depression symptom dimension), on both Day 14 and Day 28 of treatment. For subgroup analysis, we categorized 11 patients with FEP, 3 with schizophreniform disorder, and 2 with FES into the same category of FEP. Baseline demographic and treatment characteristics of the early psychosis subgroups are summarized in Supplemental Table S1 and detailed information on prior medication exposure in the short-exposure group is provided in Supplemental Table S2.

Table 1.

Baseline demographic and follow-up clinical characteristics.

	Baseline		Day14^a	Day28^a
Demographic data and clinical features	Early psychosis (n = 30)	Healthy controls (HCs; n = 30)	Early psychosis (n = 30)	Early psychosis (n = 30)
Sex (F/M)^b	15/15	15/15
Age (years, ±SD)^c	27.8 ± 7.7	28.6 ± 6.4
Education (years, ±SD)^c	14.4 ± 2.7	15.5 ± 2.2
Duration of untreated psychosis (days, ±SD)	160.1 ± 218.7
PANSS delusion/hallucination	23.0 ± 5.6		17.0 ± 6.1*	14.9 ± 4.0*
PANSS negative	15.40 ± 6.65		12.2 ± 6.0*	11.6 ± 4.8*
PANSS disorganized	14.73 ± 4.32		11.4 ± 4.6*	10.8 ± 3.2*
PANSS UHE	7.00 ± 2.23		5.0 ± 1.7*	4.5 ± 1.2*
PANSS anxiety/depression	9.63 ± 2.36		7.4 ± 2.8*	7.0 ± 2.8*
PANSS total	69.97 ± 15.80		54.9± 15.8*	48.9 ± 13.2*
Aripiprazole mean dose (mg)	6.88 ± 3.53

PANSS: the positive and negative syndrome scale; UHE: uncontrolled hostility/excitement.

Early psychosis at day14 versus baseline, paired t-test or at Day 28 versus baseline, paired t-test.

Early psychosis at baseline versus HC, chi-square test.

Early psychosis at baseline versus HC, independent t-test.

p < 0.001.

ALFF and LCOR change after aripiprazole treatment

At baseline, the ALFF and LCOR of all brain regions in patients showed no significant differences from those of HCs. After treatment, patients demonstrated significant increases in ALFF and LCOR in the bilateral putamen, as well as in the left caudate nucleus compared to baseline (Figure 1(a) and (b)). Furthermore, significant post-treatment increases in ALFF were observed in the left anterior cingulate cortex, while LCOR showed significant increases in the right post-central gyrus and right central operculum (Figure 1(a) and (b)). The relationship between the ALFF and LCOR findings and clinical severity was further explored through correlation analyses. Exploratory analyses of baseline ALFF and LCOR in relation to symptom dimensions are presented in Supplemental Table S3. At the uncorrected level (p < 0.05), associations were observed mainly for delusion/hallucination and disorganized symptoms across putaminal and related regions. After FDR correction, significant associations remained for LCOR in the left putamen with delusion/hallucination symptoms, in the right putamen with disorganized symptoms, and in the right post-central gyrus with delusion/hallucination symptoms. No significant associations were observed between baseline ALFF measures and negative symptoms, and LCOR measures were not significantly associated with negative symptoms after correction for multiple comparisons. Exploratory correlations between changes in ALFF/LCOR and symptom improvement after aripiprazole treatment are shown in Supplemental Table S4. At the uncorrected level (p < 0.05), increases in ALFF in the left putamen and increases in LCOR in the right central operculum showed associations with improvement in disorganized and negative symptoms, respectively. However, none of these associations remained significant after FDR correction. The detailed results of these exploratory correlation analyses, including uncorrected and FDR-corrected p-values, are provided in Supplemental Tables S3 and S4.

SBC changes after aripiprazole treatment

Further SBC analyses were conducted using the bilateral DCP, DRP, VRP, and the bilateral thalamus as seeds. At baseline, brain-wise analyses showed the FC values were significantly different in patients compared to HCs between the left DCP and the right angular gyrus, left posterior middle temporal gyrus, and right thalamus, between the left DRP and the right lateral occipital cortex, between the left VRP and the left post-central gyrus, between the right VRP and the bilateral putamen, between the bilateral thalamus and the left precentral gyrus, right anterior cingulate cortex, and bilateral putamen. The detailed results were listed in Table 2. To examine the potential influence of prior medication exposure, we repeated the baseline versus HC analyses with baseline cumulative chlorpromazine-equivalent dose before MRI entered as a covariate. The overall pattern of findings remained largely unchanged (Supplemental Table S5). In exploratory subgroup analyses, baseline seed-based FC was compared between the UHR subgroup and controls, and between the FEP subgroup and controls. Detailed results are presented in Supplemental Table S6. The FEP subgroup demonstrated more widespread functional dysconnectivity relative to the UHR subgroup. Dysconnectivity within and between the bilateral putamen was observed exclusively in the FEP subgroup, while thalamo–sensorimotor dysconnectivity was consistently detected across both subgroups.

Table 2.

The brain regions with significantly different FC between the baseline of early psychosis patients and HCs.

Seed	Brain regions	FC	Cluster	Coordinate			Z
Seed	Brain regions	FC	Size	x	y	z	Z
Baseline vs healthy control
L. DCP	R. Angular gyrus	↑	77	54	−52	48	3.90
	L. pMiddle temporal gyrus	↑	64	−68	−24	−22	4.31
	R. Angular gyrus	↑	60	56	−56	28	3.80
	R. Thalamus	↓	55	4	−30	12	−3.80
L. DRP	R. Lateral occipital cortex	↑	59	38	−66	52	4.31
L. VRP	L. Post-central gyrus	↑	67	−62	−10	42	4.11
R. VRP	L. Putamen	↓	250	−18	−2	8	−4.87
R. VRP	R. Putamen	↓	231	32	−16	4	−4.52
L. Thalamus	L. Precentral gyrus	↑	465	−42	−14	30	4.28
	R. Anterior cingulate cortex	↓	122	4	20	30	−4.00
	R. Putamen	↓	94	32	−18	6	−4.59
	R. Putamen	↓	85	22	12	−6	−3.99
	L. Putamen	↓	45	−20	6	−8	−3.97
R. Thalamus	L. Precentral gyrus	↑	615	−46	−8	38	4.37
	R. Anterior cingulate cortex	↓	274	4	20	30	−4.35
	R. Putamen	↓	98	12	10	2	−4.02
	L. Putamen	↓	52	−18	6	−6	−4.16

DCP: dorsal caudal putamen; DRP: dorsal rostral putamen; FC: functional connectivity; HC: healthy control; VRP: ventral rostral putamen; L: left; R: Right.

Following aripiprazole treatment, brain-wise analyses showed the FC values between the six putamen seeds and the bilateral putamen were all significantly increased in patients (Figure 2(a)–2(f), Table 3). Besides, the FC values between the left DCP and the left caudate nucleus, left superior parietal lobe, left precentral gyrus, right central opercular cortex, and right superior temporal gyrus, and between the right DCP and the left supramarginal gyrus, between the right DRP and the right orbitofrontal cortex, between the left VRP and the left Heschl’s gyrus, were also significantly changed in patients after treatment (Table 3). Following aripiprazole treatment, brain-wise analyses showed the FC values between the bilateral thalamus and the right post-central gyrus were significantly decreased in patients (Figure 2(g), (h), Table 3). Additionally, FC between the right thalamus and the right supramarginal gyrus showed a significant increase after treatment (Figure 2(h), Table 3).

Table 3.

The brain regions with significant changes of function connectivity following aripiprazole treatment.

Seed	Brain regions	FC	Cluster	Coordinate			Z
Seed	Brain regions	FC	Size	x	y	z	Z
After vs baseline
L. DCP	R. Putamen	↑	308	10	−6	22	4.64
	L. Putamen	↑	130	−30	−6	0	4.24
	L. Caudate	↑	69	−10	−8	20	4.31
	L. Superior parietal lobe	↑	50	−46	−46	60	4.09
	L. Precentral gyrus	↓	116	−56	−6	18	−3.78
	R. Central opercular cortex	↓	63	46	−10	22	−4.14
	R. Superior temporal gyrus	↓	59	52	−30	4	−4.41
R. DCP	R. Putamen	↑	430	26	−6	10	5.31
	L. Putamen	↑	329	−24	−8	10	4.49
	L. Supramarginal gyrus	↑	43	−60	−38	46	3.83
L. DRP	R. Putamen	↑	200	22	−6	16	4.57
L. DRP	L. Putamen	↑	46	−24	−4	12	4.02
R. DRP	R. Putamen	↑	298	20	−4	14	5.44
	L. Putamen	↑	228	−20	−6	2	4.64
	R. Orbitofrontal cortex	↑	48	10	32	−30	4.48
L. VRP	R. Putamen	↑	264	18	12	−4	5.02
	L. Putamen	↑	215	−18	10	−4	4.60
	L. Heschl’s gyrus	↑	84	−44	−24	4	4.12
R. VRP	L. Putamen	↑	185	−20	10	−6	4.61
R. VRP	R. Putamen	↑	170	20	10	−8	4.54
L. Thalamus	R. Post-central gyrus	↓	57	12	−38	72	−4.40
R. Thalamus	R. Supramarginal gyrus	↑	54	46	−40	44	3.82
R. Thalamus	R. Post-central gyrus	↓	65	12	−38	72	−4.69

DCP: dorsal caudal putamen; DRP: dorsal rostral putamen, VRP: ventral rostral putamen; L: left; R: right.

In a sensitivity analysis additionally controlling for baseline cumulative chlorpromazine-equivalent dose before MRI in the short-exposure subgroup, the overall pattern of increased seed-to-putamen connectivity remained, although findings involving cortical regions were less consistent (Supplemental Table S7). In exploratory subgroup analyses, a consistent increase in FC within and between the bilateral putamen was observed following aripiprazole treatment in both the UHR and FEP subgroups (Supplemental Table S8).

Exploratory correlation analyses between seed-based FC and baseline clinical symptoms are presented in Supplemental Table S9. At the uncorrected level (p < 0.05), associations were observed mainly between intra-putaminal connectivity and disorganized symptoms. However, none of these associations remained significant after FDR correction. At the uncorrected level (p < 0.05), increases in FC between the right VRP and the left putamen were positively correlated with reductions in delusion/hallucination and uncontrolled hostility/excitement symptoms, and increases in FC between the right VRP and the right putamen were positively correlated with reductions in delusion/hallucination symptoms (Figure 3). However, none of these correlations remained significant after FDR correction.

Discussion

This study investigated changes of the FC in early psychosis patients following aripiprazole treatment, with a particular focus on the putamen and thalamus. At baseline, compared to HCs, patients showed hypoconnectivity within and between the bilateral putamen, between the putamen and thalamus, and between the thalamus and the node of SN, specifically the anterior cingulate cortex. In contrast, patients exhibited hyperconnectivity between the putamen and the node of DMN (specifically the angular gyrus), the node of SM network (the post-central gyrus), and cortical regions involved in sensory integration (including the lateral occipital cortex and posterior middle temporal gyrus). Additionally, hyperconnectivity was observed between the thalamus and the node of SM (the precentral gyrus). Following aripiprazole treatment, the most consistent changes were increased ALFF and LCOR in both putamina, together with enhanced FC within each putamen and between the left and right putamen. Notably, exploratory analyses suggested that some symptom dimensions may relate differently to treatment-associated imaging changes. Increased ALFF in the left putamen may be more closely linked to disorganization, whereas increased LCOR in the right central operculum may relate more to negative symptoms. However, these associations did not remain significant after correction for multiple comparisons. After treatment, significant increases in FC were observed between the putamen and the caudate nucleus, as well as with nodes of SN, specifically the supramarginal gyrus (Krönke et al., 2020) and superior parietal lobe (Alahmadi, 2021). In contrast, FC significantly decreased between the putamen and the node of SM, the precentral gyrus, as well as between the putamen and cortical regions involved in sensory integration, including the central opercular cortex and superior temporal gyrus. As for the thalamic connectivity, FC between the thalamus and the node of SM (the post-central gyrus) significantly decreased, whereas connectivity between the thalamus and the node of SN (the supramarginal gyrus) increased after treatment.

Our results demonstrate that aripiprazole treatment can normalize the abnormal FC within and between the bilateral putamen, between the putamen and the SM, and between the thalamus and both the SN and SM in the early stages of psychosis. Moreover, we found that alterations in FC within the putamen were not only alleviated after aripiprazole treatment, but the extent of this normalization was also associated with the degree of reduction in positive symptom severity. To the best of our knowledge, this is the first study to analyze the effects of aripiprazole on early psychosis patients (FEP and UHR) using ALFF, LCOR, and seed-based analyses.

ALFF is considered a biomarker for spontaneous brain activity (Yang et al., 2007). A recent meta-analysis revealed higher ALFF in the bilateral putamen in schizophrenia (Fortier et al., 2024), and in the right striatum in FEP (Cattarinussi et al., 2023). However, some rs-fMRI studies in individuals at UHR using ALFF or fractional ALFF as indicators reported no significant differences compared to HCs (Fryer et al., 2016; Zhao et al., 2018). LCOR is another biomarker that provides insights into brain topology based on hemodynamic responses (Deshpande et al., 2009). Our study did not find any significant differences of the ALFF and LCOR across all brain regions of early psychosis patients compared to HCs. The negative result may result from our heterogeneous sample (UHR, FEP, schizophreniform, and FES). The increase in ALFF in the striatum after dopamine-serotonin receptor partial agonist treatment in our study is consistent with the finding of Lui et al. (2010). Similarly, Zhang et al. (2023) reported increased regional homogeneity (ReHo) in the bilateral caudate and putamen after 2-month treatment with dopamine receptor-targeting medications in FEP, which parallels the increased LCOR, a similar index as ReHo, in the bilateral putamen and left caudate in our study. All the three studies showed dopamine receptor-targeting medications may increase and synchronize the local brain activity of the striatum.

Previous studies have demonstrated that the putamen in the non-controlling hemisphere activates during motor task execution, suggesting FC between the bilateral putamen under physiological conditions (Marchand et al., 2008). The putamen is functionally subdivided, with distinct roles attributed to its different regions (Draganski et al., 2008). The dorsal putamen is primarily linked to cognitive impairments in psychosis due to its involvement in striato-frontal circuits and higher-order cognitive functions (Pantelis et al., 1997). In contrast, the ventral putamen plays a key role in associative learning and reward-based decision-making, both of which are commonly impaired in psychosis (Corlett et al., 2007; Kapur et al., 2005). The rostral putamen, closely connected to the prefrontal cortex, is engaged in cognitive tasks, whereas the caudal putamen is associated with SM functions (Draganski et al., 2008). Cortico-striatal dysconnectivity has been reported in both FEP (Fornito et al., 2013; Fryer et al., 2022; Nelson et al., 2022; Oh et al., 2020; Zhang et al., 2023) and UHR (Dandash et al., 2014; Li et al., 2019b; Wang et al., 2024). Our findings of hypoconnectivity between the putamen and thalamus were consistent with those of Dandash et al. (2014), who reported lower FC between the dorsal putamen and left thalamus in UHR patients, and Wang et al. (2024), who reported lower FC between the left thalamus and right putamen in both FES and UHR patients. Our findings of hyperconnectivity between the putamen and SM align with those reported by Fornito et al. (2013), which revealed higher FC between the DCP and PostCG. However, findings regarding FC between the striatum and DMN have been inconsistent. Hypoconnectivity was reported by Nelson et al. (2022) in FEP and by Hu et al. (2024) in FES, whereas hyperconnectivity was found by Huang et al. (2018) in FES and in our study.

Our findings of hypoconnectivity between and within the bilateral striatum are consistent with previous studies. Nelson et al. (2022) reported reduced FC between the bilateral caudate and left putamen and caudate itself in FEP. Similarly, Dandash et al. (2014) found decreased FC between the dorsal putamen and lenticular nucleus in UHR. In line with these results, Huang et al. (2018) reported a lower degree of centrality in the bilateral putamen in FES patients.

The thalamus serves as a critical hub for information integration, responsible for filtering external and internal stimuli, and is considered to play a pivotal role in the pathophysiology of psychosis (Onofrj et al., 2023). Previous studies have reported increased thalamic FC with multiple sensory-motor regions, including the bilateral precentral and post-central gyrus, middle and inferior occipital gyrus, and middle and superior temporal gyrus, in both chronic and early-stage schizophrenia (Ferri et al., 2018; Fryer et al., 2022). Similar thalamic hyperconnectivity, though involving less diffuse SM regions, has been observed in FEP (Zhang et al., 2023) and UHR (Ferri et al., 2018; Fryer et al., 2022). Conversely, hypoconnectivity between the thalamus and SN has been reported in both FEP (Kwak et al., 2021) and UHR (Anticevic et al., 2015; Wang et al., 2024). Consistent with these findings, we also observed hyperconnectivity between the thalamus and the precentral gyrus, as well as hypoconnectivity between the thalamus and the anterior cingulate cortex.

The most consistent findings were that, following aripiprazole treatment, the ALFF and LCOR in the bilateral putamen, as well as FC within and between bilateral putamen, were significantly increased. In contrast, FC between the bilateral thalamus and the right post-central gyrus were significantly decreased. Increases in ALFF and in FC between the right VRP and bilateral putamen were associated with the degree of positive symptom improvement. Previous studies have reported elevation of dopamine transmission, particularly in the dorsal striatum, in UHR patients (Fusar-Poli et al., 2011; Howes et al., 2009). According to our findings and those of previous studies (Dandash et al., 2014; Nelson et al., 2022), this elevation of dopamine in the striatum may contribute to reduced FC in early psychosis. In our study, this hypoconnectivity was corrected following aripiprazole treatment, and the extent of change was related to treatment response. These findings suggest that reduced FC within and between the striatum may be relate to increased dopaminergic activity, and aripiprazole may normalize the disrupted FC by modulating the dopamine transmission, thereby exerting short-term therapeutic effects on positive symptoms in early psychosis.

To better understand our findings on the effects of dopamine-serotonin receptor partial agonist treatment on brain FC, we compared them with previous studies that used similar methodologies and patient samples, that is, the studies of FC between the striatum, the thalamus, and other brain regions in FES (Feng et al., 2024; Hu et al., 2024; Lui et al., 2010; Sarpal et al., 2015) and in FEP (Chopra et al., 2021b; Zhang et al., 2023). After short-term treatment with dopamine receptor-targeting medications in FES, Sarpal et al. (2015) reported a significant increase in FC between the right ventral caudate and left thalamus. Hu et al. (2024) found decreased FC between subregions of the putamen and several cortical regions, while Lui et al. (2010) observed increased ALFF in multiple regions, including the right caudate. In our study, we observed increased ALFF in the bilateral putamen and left caudate after treatment. Regarding associations with clinical improvement, Sarpal et al. (2015) reported that changes in cortico-striatal FC were linked to reductions in positive symptoms, whereas Hu et al. (2024) found no association. Lui et al. (2010) reported increased regional ALFF was associated with improvement in positive symptoms. Similarly, our study showed increased ALFF in the left putamen was associated with reductions in disorganized symptoms. Feng et al. (2024) reported decreased within-network FC across all 7 resting-state networks, including the subcortical network, after 12 weeks of aripiprazole treatment in FES. Most between-network FC also decreased, and reductions in subcortical network FC were associated with improvements in negative symptoms and general psychopathology. In contrast, our study observed increased FC within and between the bilateral putamen after treatment. Exploratory analyses suggested that these changes may be related to improvement in positive symptom dimensions in early psychosis, although these associations did not survive correction for multiple comparisons. In terms of thalamic connectivity, Chopra et al. (2021b) revealed increased FC primarily between the thalamus and other brain regions after 3 months of dopamine receptor-targeting medication treatment in FEP, whereas our study found decreased FC between the thalamus and the post-central gyrus. In summary, consistent with previous research, our results support that striatal and thalamus FC is modulated by dopamine receptor-targeting medication treatment, while findings across studies vary in terms of direction and brain regions involved, which may result from the different methodologies for fMRI analysis and different sample characteristics. More broadly, modulation of putaminal and network-level connectivity may reflect a mechanism that is not limited to early psychosis, but may also be relevant to other conditions in which aripiprazole has shown clinical utility, including dual disorders (Martinotti et al., 2022) and treatment-resistant depression (Cavallotto et al., 2025). Many report that FC changes are associated with improvements in positive symptomatology, aligning with our current results.

Beyond the increased inter-putaminal FC, our analysis also revealed increased putaminal FC with the left superior parietal lobule, left supramarginal gyrus, and right orbitofrontal cortex, along decreased FC with the left precentral gyrus, right central opercular cortex, and right superior temporal gyrus. Although Chopra et al. (2021a) did not list individual nodes, they reported treatment-related increases in FC within the cortical–limbic network (which includes the orbitofrontal cortex) and the dorsal attention network (which includes the superior parietal lobule and supramarginal gyrus), findings that are consistent with our node-level results. Finally, the post-treatment reductions in putamen–somatosensory/auditory FC (precentral gyrus, central opercular cortex, superior temporal gyrus) observed in our cohort parallel the decreases reported by Feng et al. (2024) in connectivity between the subcortical and somatosensory networks after dopamine receptor-targeting medication treatment (Feng et al., 2024).

Surprisingly, few studies have reported effects of dopamine receptor-targeting medications on the thalamo-cortical connectivity in schizophrenia. Yang et al. (2023) reported that the dynamic FC variance between the ventral posterior-lateral portion of thalamus and the right medial orbital superior frontal gyrus, as well as the right dorsolateral superior frontal gyrus, decreased after 12-week risperidone treatment in FES. In contrast, our results showed decreased FC between the thalamus and the post-central gyrus decreased and increased FC between the thalamus and the supramarginal gyrus increased after aripiprazole treatment in early stage psychosis.

This study has several limitations. First, due to the study design, follow-up fMRI scans were not conducted for the HC group, making it unable to rule out potential time effects on FC. In addition, because the study did not include a placebo group or an active comparator, the longitudinal findings cannot be attributed exclusively to drug-specific effects and may partly reflect spontaneous clinical improvement or natural illness progression. However, considering that the participants’ mean age was close to 30 years, a stage of relatively stable brain development (Edde et al., 2021), and the study duration was about 6 weeks, the time effect is likely negligible on this timescale. Another limitation is the heterogeneity of the early psychosis patients in this study, which included UHR, FEP, schizophreniform disorder, and FES. This heterogeneity may have contributed to variability in the observed striatal–thalamic connectivity patterns because these subgroups may differ in symptom severity, illness progression, and prior treatment exposure. Exploratory subgroup analyses suggested that treatment-related increases in putamen connectivity were observable in both UHR and FEP, with a more evident pattern in FEP. These analyses were limited by small sample size and should be interpreted cautiously. In addition, the relatively short follow-up period is more likely to capture early state-related treatment effects, whereas baseline differences between patients and HCs may better reflect trait-level abnormalities. However, the present design does not allow a definitive separation between state-related and trait-level effects. Nevertheless, previous studies have indicated overlapping functional and structural changes across these subgroups (Wang et al., 2024; Witthaus et al., 2009). Therefore, our study still contributes to an enhanced understanding of the pathophysiology of early-stage psychosis and the mechanisms of aripiprazole. In addition, side effects were monitored clinically during follow-up, but standardized side-effect scales were not systematically collected, limiting our ability to examine associations between treatment-related FC changes and specific adverse effects. Follow-up PANSS assessments and MRI scans were also not perfectly temporally aligned, so associations between imaging changes and symptom improvement should be interpreted cautiously.

Conclusion

In summary, our study found that the ALFF and LCOR of the bilateral putamen and left caudate, as well as the FC within and between bilateral putamen, were significantly increased following short-term aripiprazole treatment in early psychosis patients. In contrast, FC between bilateral thalamus and post-central gyrus significantly decreased. Moreover, exploratory analyses suggested that changes in FC within and between bilateral putamen may be related to improvement in positive symptoms. However, because these correlations did not survive correction for multiple comparisons, this interpretation should be considered preliminary. These findings provide valuable insights into early brain changes in schizophrenia and may inform the development of future treatment strategies.

Supplemental Material

sj-docx-1-jop-10.1177_02698811261464518 – Supplemental material for The role of aripiprazole in modulating putamen and thalamus functional connectivity in early psychosis patients

Supplemental material, sj-docx-1-jop-10.1177_02698811261464518 for The role of aripiprazole in modulating putamen and thalamus functional connectivity in early psychosis patients by Chi Chen, I-Fei Chen, Wan-Chen Chang, Chen-Chung Liu, Ming H. Hsieh, Tzung-Jeng Hwang, Hai-Gwo Hwu, Yi-Ting Lin, Pei-Chi Tu and Chih-Min Liu in Journal of Psychopharmacology

Footnotes

Acknowledgements

The authors gratefully acknowledge the assistance of the Department of Medical Research at the National Taiwan University Hospital.

ORCID iDs

Chi Chen

I-Fei Chen

Tzung-Jeng Hwang

Chih-Min Liu

Ethical considerations

This study involved human participants and was conducted in accordance with the Declaration of Helsinki and relevant institutional guidelines. The study protocol was reviewed and approved by the Research Ethics Committee of National Taiwan University Hospital, Taipei, Taiwan. All procedures involving human participants were carried out in accordance with the ethical standards of this committee and the participating institutions.

Consent to participate

All participants provided written informed consent to participate in the study after receiving a full explanation of the aims, procedures, and possible risks and benefits.

Consent for publication

This manuscript does not contain any individual person data in any form, including images, videos, or other identifying information.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by grants from the National Science and Technology Council (NSC 100-2321-B-002-0-16, MOST 111-2314-B-002-101-MY3, 111-2314-B-075-017, and 112-2314-B-075-014-MY2), the National Taiwan University Hospital (NTUH 110-34 and 112-S0148), the Taipei Veterans General Hospital (VN107-17 and VN110-05), and the Department of Health, Taipei City Government (114XDAA00055).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

Individual-level data are not publicly available in order to protect participant confidentiality and comply with the approved ethics protocol. Summary results are provided in the article and supplements. Supplementary information is available on the Journal’s website.

Supplemental material

Supplemental material for this article is available online.

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