The complexity of brain activity reflects its ability to process information, adapt to environmental changes, and transition between states. However, it remains unclear how schizophrenia (SZ) affects brain activity complexity, particularly its dynamic changes. This study aimed to investigate the abnormal patterns of brain activity complexity in SZ, their relationship with cognitive deficits, and the impact of antipsychotic medication. Forty-four drug-naive first-episode (DNFE) SZ patients and thirty demographically matched healthy controls (HC) were included. Functional MRI-based sliding window analysis was utilized for the first time to calculate weighted permutation entropy to characterize complex patterns of brain activity in SZ patients before and after 12 weeks of risperidone treatment. Results revealed reduced complexity in the caudate, putamen, and pallidum at baseline in SZ patients compared to HC, with reduced complexity in the left caudate positively correlated with Continuous Performance Test (CPT) and Category Fluency Test scores. After treatment, the complexity of the left caudate increased. Regions with abnormal complexity showed decreased functional connectivity, with complexity positively correlated with connectivity strength. We observed that the dynamic complexity of the brain exhibited the characteristic of spontaneous, recurring \"complexity drop\", potentially reflecting transient state transitions in the resting brain. Compared to HC, patients exhibited reduced scope, intensity, and duration of complexity drop, all of which improved after treatment. Reduced duration was negatively correlated with CPT scores and positively with clinical symptoms. The results suggest that abnormalities in brain activity complexity and its dynamic changes may underlie cognitive deficits and clinical symptoms in SZ patients. Antipsychotic treatment partially restores these abnormalities, highlighting their potential as indicators of treatment efficacy and biomarkers for personalized therapy.

Physical pain and negative emotions represent two distinct drinking motives that contribute to harmful alcohol use. Proactive avoidance, in contrast, can reduce consumption in response to these motives but appears to be impaired in those with problem drinking. Despite such evidence, proactive avoidance and its underlying neural deficits have not been assessed experimentally. How these deficits inter-relate with drinking motives to influence alcohol use also remains unclear. The current study leveraged neuroimaging data in forty-one problem and forty-one social drinkers who performed a probabilistic learning go/nogo task featuring proactive avoidance of painful outcomes. We identified the brain responses to proactive avoidance and contrasted the neural correlates of drinking to avoid negative emotions vs. physical pain. Behavioral results confirmed proactive avoidance deficits in problem drinking individuals\' learning rate and performance accuracy, both which were associated with greater alcohol use. Imaging findings in the problem drinking group showed that negative emotions as a drinking motive predicted attenuated right anterior insula activation during proactive avoidance. In contrast, physical pain motive predicted reduced right putamen response. These regions\' activations as well as functional connectivity with the somatomotor cortex also demonstrated a negative relationship with drinking severity and positive relationship with proactive avoidance performance. Path modeling further delineated the pathways through which physical pain and negative emotions influenced the neural and behavioral measures of proactive avoidance. Taken together, the current findings provide experimental evidence for proactive avoidance deficits in alcohol misuse and establish the link between their neural underpinnings and drinking behavior.

Genetic generalized epilepsies (GGE) exhibit widespread morphometric alterations in the subcortical structures. Subcortical structures are essential for understanding GGE pathophysiology, but their fine-grained morphological diversity has yet to be comprehensively investigated. Furthermore, the relationships between macroscale morphological disturbances and microscale molecular chemoarchitectures are unclear. High-resolution structural images were acquired from patients with GGE (n = 97) and sex- and age-matched healthy controls (HCs, n = 184). Individual measurements of surface shape features (thickness and surface area) of seven bilateral subcortical structures were quantified. The patients and HCs were then compared vertex-wise, and shape anomalies were co-located with brain neurotransmitter profiles. We found widespread morphological alterations in GGE and prominent disruptions in the thalamus, putamen, and hippocampus. Shape area dilations were observed in the bilateral ventral, medial, and right dorsal thalamus, as well as the bilateral lateral putamen. We found that the shape area deviation pattern was spatially correlated with the norepinephrine transporter and nicotinic acetylcholine (Ach) receptor (α4β2) profiles, but a distinct association was seen in the muscarinic Ach receptor (M1). The findings provided a comprehensive picture of subcortical morphological disruptions in GGE, and further characterized the associated molecular mechanisms. This information may increase our understanding of the pathophysiology of GGE.

A woman in her 70s presented with approximately 2 years of sudden-onset gait and cognitive problems. She had been diagnosed with normal pressure hydrocephalus (NPH) and underwent ventriculoperitoneal shunt (VPS) placement 1 year prior. Before VPS placement, brain imaging showed ventriculomegaly and chronic infarction of the right putamen and claustrum. A lumbar drain trial resulted in modest improvement of gait dysfunction. She underwent VPS placement for suspected NPH, but her symptoms remained unchanged. Examination revealed mild cognitive impairment, left-sided and lower body predominant parkinsonism, as well as disproportionately prominent postural instability. Gait analysis showed increased gait variability, reduced velocity and shortened step length bilaterally. Motor and gait abnormalities did not change after administration of levodopa. Her symptoms have remained stable for up to 52 months since symptom onset. We postulate that the infarction affecting the right putamen and claustrum could have led to a higher-level gait disorder mimicking NPH.

UNASSIGNED: Schizophrenia is often associated with volumetric reductions in cortices and expansions in basal ganglia, particularly the putamen. Recent genome-wide association studies have highlighted the significance of variants in the 3\' regulatory region adjacent to the kinectin 1 gene (KTN1) in regulating gray matter volume (GMV) of the putamen. This study aimed to comprehensively investigate the involvement of this region in schizophrenia.
UNASSIGNED: We analyzed 1136 single-nucleotide polymorphisms (SNPs) covering the entire 3\' regulatory region in 4 independent dbGaP samples (4604 schizophrenia patients vs. 4884 healthy subjects) and 3 independent Psychiatric Genomics Consortium samples (107 240 cases vs. 210 203 controls) to identify consistent associations. Additionally, we examined the regulatory effects of schizophrenia-associated alleles on KTN1 mRNA expression in 16 brain areas among 348 subjects, as well as GMVs of 7 subcortical nuclei in 38 258 subjects, and surface areas (SA) and thickness (TH) of the entire cortex and 34 cortical areas in 36 936 subjects.
UNASSIGNED: The major alleles (f > 0.5) of 25 variants increased (β > 0) the risk of schizophrenia across 2 to 5 independent samples (8.4 × 10-4 ≤ P ≤ .049). These schizophrenia-associated alleles significantly elevated (β > 0) GMVs of basal ganglia, including the putamen (6.0 × 10-11 ≤ P ≤ 1.1 × 10-4), caudate (8.7 × 10-4 ≤ P ≤ 9.4 × 10-3), pallidum (P = 6.0 × 10-4), and nucleus accumbens (P = 2.7 × 10-5). Moreover, they potentially augmented (β > 0) the SA of posterior cingulate and insular cortices, as well as the TH of frontal (pars triangularis and medial orbitofrontal), parietal (superior, precuneus, and inferior), and temporal (transverse) cortices, but potentially reduced (β < 0) the SA of the whole, frontal (medial orbitofrontal), and temporal (pole, superior, middle, and entorhinal) cortices, as well as the TH of rostral middle frontal and superior frontal cortices (8.9 × 10-4 ≤ P ≤ .050).
UNASSIGNED: Our findings identify significant and functionally relevant risk alleles in the 3\' regulatory region adjacent to KTN1, implicating their crucial roles in the development of schizophrenia.

The putamen has been proposed to play a critical role in the development of obsessive-compulsive disorder (OCD). The primary objective of this study was to examine the resting-state regional activity and functional connectivity patterns of the putamen in individuals diagnosed with OCD. To achieve this, we employed resting-state functional magnetic resonance imaging (rs-fMRI) to collect data from a sample of 45 OCD patients and 53 healthy control participants. We aimed to use the regional amplitude of low-frequency fluctuation (ALFF) analysis to generate the ROI masks of the putamen and then conduct the whole brain functional connectivity of the putamen in individuals with OCD. Compared to controls, the OCD group demonstrated decreased ALFF in bilateral putamen. The right putamen also displayed decreased FC with the left putamen extending to the inferior frontal gyrus (IFG), bilateral precuneus extending to calcarine, the right middle occipital cortex extending to the right middle temporal cortex, and the left middle occipital gyrus. The decreased connectivity between the right putamen and the left IFG was negatively correlated with Yale-Brown Obsessive Compulsive scale (Y-BOCS) Obsession Scores. This study aimed to reveal the putamen changes in resting-state activity and connectivity in OCD patients, highlighting the significance of aberrant ALFF/FC of the putamen is a key characteristic of OCD.

OBJECTIVE: The objective of this study was to develop and evaluate the feasibility and safety of a novel transaxial surgical approach for the delivery of human induced pluripotent stem cell-derived dopaminergic neuroprogenitor cells (DANPCs) into the putamen nucleus using nonhuman primates and surgical techniques and tools relevant to human clinical translation.
METHODS: Nine immunosuppressed, unlesioned adult cynomolgus macaques (4 females, 5 males) received intraputaminal injections of vehicle or DANPCs (0.9 × 105 to 1.1 × 105 cells/µL) under real-time intraoperative MRI guidance. The infusates were combined with 1-mM gadoteridol (for intraoperative MRI visualization) and delivered via two tracks per hemisphere (ventral and dorsal) using a transaxial approach. The total volumes of infusion were 25 µL and 50 µL for the right and left putamen, respectively (infusion rate 2.5 µL/min). Animals were evaluated with a battery of clinical and behavioral outcome measures and euthanized 7 or 30 days postsurgery; full necropsies were performed by a board-certified veterinary pathologist. Brain tissues were collected and processed for immunohistochemistry, including against the human-specific marker STEM121.
RESULTS: The optimized surgical technique and tools produced successful targeting of the putamen via the transaxial approach. Intraoperative MR images confirmed on-target intraputaminal injections in all animals. All animals survived to scheduled termination without clinical evidence of neurological deficits. The first 4 animals to undergo surgery had mild brain swelling noted at the end of surgery, of which 3 had transient reduced vision; administration of mannitol therapy and reduced intravenous fluid during the surgical procedure addressed these complications. Immunostaining against STEM121 confirmed the presence of grafted cells along the injection track within the targeted putamen area of DANPC-treated animals. All adverse histological findings were limited in scope and consistent with surgical manipulation, injection procedure, and postsurgical inflammatory response to the mechanical disruption caused by the cannula insertion.
CONCLUSIONS: The delivery system, injection procedure, and DANPCs were well tolerated in all animals. Prevention of mild brain swelling by mannitol dosing and reduction of intravenous fluids during surgery allowed visual effects to be avoided. The results of the study established that this novel transaxial approach can be used to correctly and safely target cell injections to the postcommissural putamen and support clinical investigation.

Deciphering the striatal interneuron diversity is key to understanding the basal ganglia circuit and to untangling the complex neurological and psychiatric diseases affecting this brain structure. We performed snRNA-seq and spatial transcriptomics of postmortem human caudate nucleus and putamen samples to elucidate the diversity and abundance of interneuron populations and their inherent transcriptional structure in the human dorsal striatum. We propose a comprehensive taxonomy of striatal interneurons with eight main classes and fourteen subclasses, providing their full transcriptomic identity and spatial expression profile as well as additional quantitative FISH validation for specific populations. We have also delineated the correspondence of our taxonomy with previous standardized classifications and shown the main transcriptomic and class abundance differences between caudate nucleus and putamen. Notably, based on key functional genes such as ion channels and synaptic receptors, we found matching known mouse interneuron populations for the most abundant populations, the recently described PTHLH and TAC3 interneurons. Finally, we were able to integrate other published datasets with ours, supporting the generalizability of this harmonized taxonomy.

BACKGROUND: Having multiple previous generations with depression in the family increases offspring risk for psychopathology. Parental depression has been associated with smaller subcortical brain volumes in their children, but whether two prior generations with depression is associated with further decreases is unclear.
METHODS: Using two independent cohorts, 1) a Three-Generation Study (TGS, N = 65) with direct clinical interviews of adults and children across all three generations, and 2) the Adolescent Brain Cognitive Development Study (ABCD, N = 10,626) of 9-10 year-old children with family history assessed by a caregiver, we tested whether having more generations of depression in the family was associated with smaller subcortical volumes (using structural MRI).
RESULTS: In TGS, caudate, pallidum and putamen showed decreasing volumes with higher familial risk for depression. Having a parent and a grandparent with depression was associated with decreased volume compared to having no familial depression in these regions. Putamen volume was associated with depression at eight-year follow-up. In ABCD, smaller pallidum and putamen were associated with family history, which was driven by parental depression, regardless of grandparental depression.
CONCLUSIONS: Discrepancies between cohorts could be due to interview type (clinical or self-report) and informant (individual or common informant), sample size or age. Future analyses of follow-up ABCD waves will be able to assess whether effects of grandparental depression on brain markers become more apparent as the children enter young adulthood.
CONCLUSIONS: Basal ganglia regional volumes are significantly smaller in offspring with a family history of depression in two independent cohorts.

[This corrects the article DOI: 10.3389/fnana.2019.00022.].