Partial ablation of frontal cortical subplate leads to developmental abnormalities in KCC2 in the prefrontal cortex.

During early brain development, the subplate relays thalamocortical afferents to the overlying cortex. Disconnection of thalamic inputs to the prefrontal cortex by lesions of the subplate of the developing prefrontal cortex at early neonatal periods result in adult-onset behavioral abnormalities reminiscent of positive, negative, and cognitive symptoms of schizophrenia. Delayed maturation of γ-amino butyric acid (GABA) function may contribute to certain abnormalities of the prefrontal cortex and clinical manifestations of schizophrenia. Lesions to the subplate have also been implicated in developmental abnormalities of GABA neurotransmission in somatosensory and visual cortices. Therefore, we sought to examine the effects of subplate lesions in the developing prefrontal cortex of rats on the expression of GABA markers [parvalbumin and glutamic acid decarboxylase (GAD67)] and proteins responsible for GABAergic synaptic maturation [potassium-chloride cotransporter (KCC2) and sodium­potassium-chloride cotransporter (NKCC1)]. Lesioned and control rats were sacrificed between postnatal days (P) 5 and 90 and immunolabeled for parvalbumin, GAD67, KCC2, and NKCC1 in the prelimbic area of the prefrontal cortex. We found decreased immunoreactivity of KCC2 on neuronal cell membranes at P11 compared to control rats. However, the overall immunoreactivity of KCC2 and NKCC1 did not differ between lesion and control animals at all time points studied. Lesioned rats also showed decreased expression of parvalbumin, but not GAD67. Our results indicate that mechanisms underlying trafficking and membrane binding of KCC2 may contribute to altered GABA receptor function during development in schizophrenia.

Olanzapine-induced methylation alters cadherin gene families and associated pathways implicated in psychosis.

BACKGROUND: The complex aetiology of most mental disorders involves gene-environment interactions that may operate using epigenetic mechanisms particularly DNA methylation. It may explain many of the features seen in mental disorders including transmission, expression and antipsychotic treatment responses. This report deals with the assessment of DNA methylation in response to an antipsychotic drug (olanzapine) on brain (cerebellum and hippocampus), and liver as a non-neural reference in a rat model. The study focuses on the Cadherin/protocadherins encoded by a multi-gene family that serve as adhesion molecules and are involved in cell-cell communication in the mammalian brain. A number of these molecules have been implicated in the causation of schizophrenia and related disorders. RESULTS: The results show that olanzapine causes changes in DNA methylation, most specific to the promoter region of specific genes. This response is tissue specific and involves a number of cadherin genes, particularly in cerebellum. Also, the genes identified have led to the identification of several pathways significantly affected by DNA methylation in cerebellum, hippocampus and liver. These included the Gα12/13 Signalling (p = 9.2E-08) and Wnt signalling (p = 0.01) pathways as contributors to psychosis that is based on its responsiveness to antipsychotics used in its treatment. CONCLUSION: The results suggest that DNA methylation changes on the promoter regions of the Cadherin/protocadherin genes impact the response of olanzapine treatment. These impacts have been revealed through the identified pathways and particularly in the identification of pathways that have been previously implicated in psychosis.

Assessment of executive function in a rodent model of Type 1 diabetes.

This study examined the impact of Type 1 Diabetes Mellitus (T1DM) on executive function using a series of operant conditioning-based tasks in rats. Sprague Dawley rats were randomized to either non-diabetic (n = 12; 6 male) or diabetic (n = 14; 6 male) groups. Diabetes was induced using multiple low-dose streptozotocin injections. All diabetic rodents were insulin-treated using subcutaneous insulin pellet implants (9-15 mM). At week 14 of the study, rats were placed on a food restricted diet to induce 5-10 % weight loss. Rodents were familiarized and their set-shifting ability was tested on a series of tasks that required continuous adjustments to novel stimulus-reward paradigms in order to receive food rewards. Results showed no differences in the number of trials, nor number and type of errors made to successfully complete each task between groups. Therefore, we report no differences in executive function, or more specifically set-shifting abilities between non-diabetic and diabetic rodents that receive insulin.

Progressive membrane phospholipid changes in first episode schizophrenia with high field magnetic resonance spectroscopy.

Patients with a first episode of schizophrenia generally have increased phospholipid membrane breakdown products within the brain, while findings in chronic patients have been inconsistent. In this study we examine progressive changes in phosphorus membrane metabolites in the same patient group through the early years of schizophrenia in brain regions associated with the disease. Sixteen never-treated and medicated first episode schizophrenic patients were assessed at 10 months and 52 months after diagnosis. Sixteen matched volunteers were assessed at baseline and after 35 months. Phospholipid membrane metabolism was assessed with phosphorous magnetic resonance spectroscopy in the thalamus, cerebellum, hippocampus, anterior/posterior cingulate, prefrontal cortex, parieto-occipital cortex, superior temporal gyrus and temporal pole. At 10 months, glycerophosphocholine was increased in the anterior cingulate in patients as compared to controls. Glycerophosphocholine was decreased in the anterior cingulate and increased in the posterior cingulate and left superior temporal gyrus; glycerophosphoethanolamine was decreased in the left thalamus and increased in the left hippocampus within patients over time. At 52 months, compared to controls phosphocholine was increased in the left thalamus and glycerophosphoethanolamine was increased in the left hippocampus. These results imply a gradual inclusion of brain regions in schizophrenia where an initial increase, followed by a decrease in phospholipid membrane metabolites was observed. This pattern, observed in the early years of schizophrenia, is consistent with excitotoxic neural membrane breakdown in these regions.

Grey matter and social functioning correlates of glutamatergic metabolite loss in schizophrenia.

BACKGROUND: Thalamic glutamine loss and grey matter reduction suggest neurodegeneration in first-episode schizophrenia, but the duration is unknown. AIMS: To observe glutamine and glutamate levels, grey matter volumes and social functioning in patients with schizophrenia followed to 80 months after diagnosis. METHOD: Grey matter volumes and proton magnetic resonance spectroscopy metabolites in left anterior cingulate and left thalamus were measured in 17 patients with schizophrenia before medication and 10 and 80 months after diagnosis. Social functioning was assessed with the Life Skills Profile Rating Scale (LSPRS) at 80 months. RESULTS: The sum of thalamic glutamate and glutamine levels decreased over 80 months, and correlated inversely with the LSPRS. Thalamic glutamine and grey matter loss were significantly correlated in frontal, parietal, temporal and limbic regions. CONCLUSIONS: Brain metabolite loss is correlated with deteriorated social functioning and grey matter losses in schizophrenia, consistent with neurodegeneration.

Characterizing the autonomic neural connections between the abdominal aortic and superior hypogastric plexuses: A multimodal neuroanatomical study.

The aortic plexus serves as the primary gateway for sympathetic fibers innervating the pelvic viscera. Damage to this plexus and/or its associated branches can lead to an assortment of neurogenic complications such as bladder dysregulation or retrograde ejaculation. The neuroanatomy of this autonomic plexus has only recently been clarified in humans; as such, the precise function of its constituent fibers is still not clear. Further study into the functional neuroanatomy of the aortic plexus could help refine nerve-sparing surgical procedures that risk debilitating neurogenic complications, while also advancing understanding of peripheral sympathetic circuitry. To this end, the current study employed an in vivo electrostimulation paradigm in a porcine model, in combination with lipophilic neuronal tracing experiments in fixed, post-mortem human tissues, to further characterize the functional neuroanatomy of the aortic plexus. Electrostimulation results demonstrated that caudal lumbar splanchnic nerves provide primary control over the porcine bladder neck in comparison to other constituent fibers within the aortic plexus. Ex vivo human data revealed that the prehypogastric ganglion contains a significant number of neurons projecting to the superior hypogastric plexus, and that these neurons are arranged in a topographic manner within the ganglion. Altogether, these findings suggest that a pivotal sympathetic pathway mediating bladder neck contraction courses through the caudal lumbar splanchnic nerves, prehypogastric and inferior mesenteric ganglia and superior hypogastric plexus.

Maternal Immune Activation Alters Fetal Brain Development and Enhances Proliferation of Neural Precursor Cells in Rats.

Maternal immune activation (MIA) caused by exposure to pathogens or inflammation during critical periods of neurodevelopment is a major risk factor for behavioral deficits and psychiatric illness in offspring. A spectrum of behavioral abnormalities can be recapitulated in rodents by inducing MIA using the viral mimetic, PolyI:C. Many studies have focused on long-term changes in brain structure and behavioral outcomes in offspring following maternal PolyI:C exposure, but acute changes in prenatal development are not well-characterized. Using RNA-Sequencing, we profiled acute transcriptomic changes in rat conceptuses (decidua along with nascent embryo and placenta) after maternal PolyI:C exposure during early gestation, which enabled us to capture gene expression changes provoked by MIA inclusive to the embryonic milieu. We identified a robust increase in expression of genes related to antiviral inflammation following maternal PolyI:C exposure, and a corresponding decrease in transcripts associated with nervous system development. At mid-gestation, regions of the developing cortex were thicker in fetuses prenatally challenged with PolyI:C, with females displaying a thicker ventricular zone and males a thicker cortical mantle. Along these lines, neural precursor cells (NPCs) isolated from fetal brains prenatally challenged with PolyI:C exhibited a higher rate of self-renewal. Expression of Notch1 and the Notch ligand, delta-like ligand 1, which are both highly implicated in maintenance of NPCs and nervous system development, was increased following PolyI:C exposure. These results suggest that MIA elicits rapid gene expression changes within the conceptus, including repression of neurodevelopmental pathways, resulting in profound alterations in fetal brain development.

Mapping brain abnormalities in boys with autism.

Children with autism spectrum disorder (ASD) exhibit characteristic cognitive and behavioral differences, but no systematic pattern of neuroanatomical differences has been consistently found. Recent neurodevelopmental models posit an abnormal early surge in subcortical white matter growth in at least some autistic children, perhaps normalizing by adulthood, but other studies report subcortical white matter deficits. To investigate the profile of these alterations in 3D, we mapped brain volumetric differences using a relatively new method, tensor-based morphometry. 3D T1-weighted brain MRIs of 24 male children with ASD (age: 9.5 years +/- 3.2 SD) and 26 age-matched healthy controls (age: 10.3 +/- 2.4 SD) were fluidly registered to match a common anatomical template. Autistic children had significantly enlarged frontal lobes (by 3.6% on the left and 5.1% on the right), and all other lobes of the brain were enlarged significantly, or at trend level. By analyzing the applied deformations statistically point-by-point, we detected significant gray matter volume deficits in bilateral parietal, left temporal and left occipital lobes (P = 0.038, corrected), trend-level cerebral white matter volume excesses, and volume deficits in the cerebellar vermis, adjacent to volume excesses in other cerebellar regions. This profile of excesses and deficits in adjacent regions may (1) indicate impaired neuronal connectivity, resulting from aberrant myelination and/or an inflammatory process, and (2) help to understand inconsistent findings of regional brain tissue excesses and deficits in autism.

Prefrontal cortical D1 dopamine receptors modulate subcortical D2 dopamine receptor-mediated stress responsiveness.

Increased responsiveness to stress plays an important role in the manifestation of schizophrenia symptoms. Evidence indicates that the prefrontal cortex (PFC), and dopamine neurotransmission in the PFC in particular, is involved in the modulation of stress responsiveness. Decreased dopaminergic activity and loss of dopamine fibres have been reported in PFC in schizophrenia patients. Consequently, it was hypothesized that depletion of dopamine in PFC may facilitate increased stress responsiveness. Adult Sprague-Dawley rats received injections of 6-hydroxydopamine or saline bilaterally into the medial PFC (mPFC) following desipramine pretreatment to selectively deplete dopaminergic fibres. Following a 3-wk recovery period, the lesioned and control rats received injections of a D1 or D2 dopamine receptor agonist or vehicle into the mPFC and were immediately subjected to forced swimming as a stressor. Results showed that frequency of locomotion and rearing, behavioural measures indicative of increased dopaminergic activity in the nucleus accumbens (NAc), were significantly increased following stress in prefrontal cortical dopamine-depleted rats. This effect was significantly ameliorated by infusions of a D1 dopamine receptor agonist directly into the mPFC in a dose-dependent manner but not by infusion of a D2 dopamine receptor agonist. In addition, stress-induced behavioural changes in prefrontal cortical dopamine-depleted rats were significantly reduced following selective discrete infusions of a D2 dopamine receptor antagonist into the NAc shell. The results suggest that dopaminergic transmission via D1 receptors in the mPFC modulates D2 dopamine receptor-mediated stress responsiveness in the NAc, a feature that may be disrupted in schizophrenia patients.

Longitudinal 4.0 Tesla (31)P magnetic resonance spectroscopy changes in the anterior cingulate and left thalamus in first episode schizophrenia.

Progressive volumetric losses in schizophrenia may be preceded by abnormal cell membrane metabolism. Longitudinal changes in membrane metabolites were quantified with (31)P MRS in the anterior cingulate and left thalamus of 13 first episode schizophrenic patients and 13 healthy volunteers at baseline and 30 months. Glycerophosphocholine was higher in patients at baseline in the anterior cingulate and glycerophosphoethanolamine was lower in the left thalamus at 30 months compared with patients at baseline and volunteers at 30 months. These observations suggest longitudinal changes in membrane metabolites consistent with a neurodegenerative process in certain cases of schizophrenia.

Botulinum toxin A injection into the entopeduncular nucleus improves dynamic locomotory parameters in hemiparkinsonian rats.

Parkinson's disease is associated with hyperactivity of the subthalamic nucleus (STN), contributing to motor and gait disturbances. Although deep brain stimulation of the STN alleviates certain motor dysfunction, its specific effect on gait abnormalities remains controversial. This study investigated the long-term changes in locomotion following direct infusions of botulinum toxin-A into the globus pallidus internal segment (GPi) to suppress the flow of information from the STN to the GPi in a hemiparkinsonian rat model. Static and dynamic gait parameters were quantified using a CatWalk apparatus. Interestingly, botulinum toxin-A at 0.5 ng significantly reduced only the dynamic gait parameters of hemiparkinsonian rats at 1 week and 1 month post-infusion, while static gait parameters did not change. This study offers new insights into the complexity of basal ganglia in locomotor control and shows the potential of central infusion of botulinum toxin-A as a novel intervention in the study of experimental hemiparkinson's disease.

Semiautomated Assessment of the Anterior Cingulate Cortex in Alzheimer's Disease.

BACKGROUND AND PURPOSE: The anterior cingulate cortex (ACC) is involved in several cognitive processes including executive function. Degenerative changes of ACC are consistently seen in Alzheimer's disease (AD). However, volumetric changes specific to the ACC in AD are not clear because of the difficulty in segmenting this region. The objectives of the current study were to develop a precise and high-throughput approach for measuring ACC volumes and to correlate the relationship between ACC volume and cognitive function in AD. METHODS: Structural T1 -weighted magnetic resonance images of AD patients (n = 47) and age-matched controls (n = 47) at baseline and at 24 months were obtained from the Alzheimer's disease neuroimaging initiative (ADNI) database and studied using a custom-designed semiautomated segmentation protocol. RESULTS: ACC volumes obtained using the semiautomated protocol were highly correlated to values obtained from manual segmentation (r = .98) and the semiautomated protocol was considerably faster. When comparing AD and control subjects, no significant differences were observed in baseline ACC volumes or in change in ACC volumes over 24 months using the two segmentation methods. However, a change in ACC volume over 24 months did not correlate with a change in mini-mental state examination scores. CONCLUSIONS: Our results indicate that the proposed semiautomated segmentation protocol is reliable for determining ACC volume in neurodegenerative conditions including AD.

Intrapallidal injection of botulinum toxin A recovers gait deficits in a parkinsonian rodent model.

AIM: Modulation of electrical activity in the subthalamic nucleus has been therapeutically effective in Parkinson's disease. Pharmacological manipulation of glutamate release from subthalamic neurons could also favourably alter basal ganglia activity to improve motor symptoms. This study investigates the efficacy of selective suppression of hyperactive glutamatergic input from the subthalamic nucleus to the globus pallidus internal segment by botulinum toxin A (BoNT-A) in a parkinsonian model. METHODS: Unilateral 6-hydroxydopamine lesioned parkinsonian rodents and controls received microinfusions of BoNT-A or vehicle into the ipsilateral internal globus pallidus (n = 8 per group). Changes in gait were measured by the CatWalk apparatus, along with assessment of apomorphine-induced rotational behaviour prior to and following BoNT-A injection. Immunofluorescent staining for markers of glutamatergic, GABAergic and total terminals was performed at the internal globus pallidus. RESULTS: Administration of a single dose of BoNT-A (0.5 ng) significantly improved the rotational asymmetry and gait abnormalities. Ameliorations in speed, body speed variation, cadence and walking pattern were comparable to pre-lesioned animals, and persisted up to 1 month following BoNT-A injection. These changes are associated to BoNT-A's ability to selectively target glutamatergic terminals. CONCLUSION: Blockade of subthalamic hyperactivity by BoNT-A leads to sufficient reorganization in the basal ganglia needed to generate a consistent rhythmic pattern of walking. This suggests the potential use of intracerebral BoNT-A to produce effective neuromodulation in the parkinsonian brain, as well as expansion into other neurodegenerative disorders linked to excitotoxity.

Δ-9-Tetrahydrocannabinol and Cannabidiol produce dissociable effects on prefrontal cortical executive function and regulation of affective behaviors.

The use of cannabis for therapeutic and recreational purposes is growing exponentially. Nevertheless, substantial questions remain concerning the potential cognitive and affective side-effects associated with cannabis exposure. In particular, the effects of specific marijuana-derived phytocannabinoids on neural regions such as the prefrontal cortex (PFC) are of concern, given the role of the PFC in both executive cognitive function and affective processing. The main biologically active phytocannabinoids, ∆-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), interact with multiple neurotransmitter systems important for these processes directly within the PFC. Considerable evidence has demonstrated that acute or chronic THC exposure may induce psychotomimetic effects, whereas CBD has been shown to produce potentially therapeutic effects for both psychosis and/or anxiety-related symptoms. Using an integrative combination of cognitive and affective behavioral pharmacological assays in rats, we report that acute intra-PFC infusions of THC produce anxiogenic effects while producing no impairments in executive function. In contrast, acute infusions of intra-PFC CBD impaired attentional set-shifting and spatial working memory, without interfering with anxiety or sociability behaviors. In contrast, intra-PFC CBD reversed the cognitive impairments induced by acute glutamatergic antagonism within the PFC, and blocked the anxiogenic properties of THC, suggesting that the therapeutic properties of CBD within the PFC may be present only during pathologically aberrant states within the PFC. Interestingly, the effects of PFC THC vs. CBD were found to be mediated through dissociable CB1 vs. 5-HT1A-dependent receptor signaling mechanisms, directly in the PFC.

Injections of NGF into neonatal frontal cortex decrease social interaction as adults: a rat model of schizophrenia.

BACKGROUND: Injection of nerve growth factor (NGF) into the developing frontal cortex (FC) has been shown to produce adult-onset subcortical dopaminergic hyperactivity, impaired prepulse inhibition of the acoustic startle response, and several neuropathological features of schizophrenia. The present study was to determine whether such lesions would lead to impaired social interaction, a prominent negative feature of schizophrenia. METHODS: Rat pups received daily injections of human recombinant NGF into the developing FC on postnatal days 1 and 2 to partially lesion subplate neurons. Lesioned rats were tested in similar-treatment pairings lasting 23.5 hours using the EthoVision behavioral monitoring system at 6 and 14 weeks of age. Brains were then perfusion fixed for histological analysis. RESULTS: Lesioned rats showed significantly increased movement, relative to controls, during the light phase at 6 weeks of age. At 14 weeks, they maintained a significantly greater mean distance apart from one another, and engaged in significantly less approach and avoidance behavior during the dark phase, relative to controls. Histological changes were consistent with those described previously in this animal model. CONCLUSION: Results indicate that injections of NGF into the developing FC of neonatal rats result in reduced social interaction, which is consistent with behaviors observed in human schizophrenia patients.

Three-dimensional mapping of the lateral ventricles in autism.

In this study, a computational mapping technique was used to examine the three-dimensional profile of the lateral ventricles in autism. T1-weighted three-dimensional magnetic resonance images of the brain were acquired from 20 males with autism (age: 10.1+/-3.5 years) and 22 male control subjects (age: 10.7+/-2.5 years). The lateral ventricles were delineated manually and ventricular volumes were compared between the two groups. Ventricular traces were also converted into statistical three-dimensional maps, based on anatomical surface meshes. These maps were used to visualize regional morphological differences in the thickness of the lateral ventricles between patients and controls. Although ventricular volumes measured using traditional methods did not differ significantly between groups, statistical surface maps revealed subtle, highly localized reductions in ventricular size in patients with autism in the left frontal and occipital horns. These localized reductions in the lateral ventricles may result from exaggerated brain growth early in life.

A gliotoxin model of occipital seizures in rats.

PURPOSE: Intracortical microinjection of fluorocitrate, a reversible inhibitor of glial tricarboxylic acid (TCA), results in impaired glial metabolism and epileptic seizures. To determine the potential contribution of epileptic activities to the metabolic properties of fluorocitrate, we investigated the seizure-inducing property of fluorocitrate at different doses. METHODS: Twenty-seven male Sprague Dawley rats (250-400g) were studied with chronically implanted electrodes and cannulae in the occipital cortices. A week after surgery, awake behaving rats were injected with 0.2microl solution containing various concentrations of fluorocitrate or saline in the right occipital cortex; two sham-treated animals did not receive an injection. EEG was recorded with implanted electrodes. Thionin staining was used to verify injection sites. Twenty rats underwent immunohistochemistry for glial fibrilary acidic protein (GFAP) and neuronal nuclear-specific antigen (NeuN) 48h after the injections. RESULTS: Seizures developed within an hour of injection in all the rats that received > or =0.8nmol fluorocitrate and 2 of 4 rats that received 0.4nmol fluorocitrate. Five of 12 animals that received > or =1.2nmol fluorocitrate experienced status epilepticus. There was a significant increase in GFAP staining at the injection site in doses > or =0.8nmol fluorocitrate. There was only mild neuronal loss revealed by NeuN staining at the injection site in the animals that had received 1.6nmol flourocitrate. CONCLUSION: This study shows that fluorocitrate results in focal epileptic seizures with secondary generalization in a dose-dependent manner, including low doses of this agent previously used for studies of brain metabolism.

Infusions of Nerve Growth Factor Into the Developing Frontal Cortex Leads to Deficits in Behavioral Flexibility and Increased Perseverance.

In the pursuit of further establishing a neurodevelopmental animal model to investigate the mechanisms underlying impaired executive function, a core and severely debilitating symptom of schizophrenia, we sought to characterize the deficits in behavioral flexibility in adult rats following neonatal infusions of nerve growth factor (NGF) into the medial part of the developing frontal cortex. Our previous studies using this neonatal frontal cortical lesion model have shown that it leads to adult-onset positive and negative symptom-like features, and several neuropathological abnormalities of schizophrenia. In the present study, we used operant conditioning-based paradigms to investigate set-shifting ability and reversal learning performance in adult rats that received infusions of NGF into the developing frontal cortex on post-natal day 1. NGF-infusion caused apoptosis of cells in the subplate layer. Adult rats that received neonatal infusions of NGF showed decreased grey matter thickness, and decreased levels of parvalbumin in prelimbic and infralimbic areas of the medial prefrontal cortex (mPFC). NGF-treated rats had difficulty completing the set-shifting and reversal learning tasks due to increased perseverance (ie, a failure to disengage from the previously-learned strategy once the rule contingencies were changed) compared to the control group. Collectively, these results identify the crucial role of the frontal cortical subplate layer in the structural and functional development of the mPFC relevant to schizophrenia. Furthermore, the present findings substantially advance the face and construct validity of this putative preclinical model of schizophrenia based on developmental disruption of the frontal cortical subplate.

Temporoparietal Junction Functional Connectivity in Early Schizophrenia and Major Depressive Disorder.

BACKGROUND: The temporoparietal junction (TPJ) has been linked to lower-level attentional and higher-level social processing, both of which are affected in schizophrenia (SZ) and major depressive disorder (MDD). We examined resting functional connectivity of bilateral anterior and posterior TPJ in SZ and MDD to evaluate potential anomalies in each disorder and differences between disorders. METHODS: Resting-state functional magnetic resonance imaging data were acquired from 24 patients with SZ, 24 patients with MDD, and 24 age-matched healthy controls. We performed seed-based functional connectivity analyses with seed regions in bilateral anterior and posterior TPJ, covarying for gender and smoking. RESULTS: SZ had reduced connectivity versus controls between left anterior TPJ and dorsolateral prefrontal cortex (dlPFC) and posterior cingulate cortex (PCC); between left posterior TPJ and middle cingulate cortex, left dorsal PFC, and right lateral PFC; between right anterior TPJ and bilateral PCC; and between right posterior TPJ and middle cingulate cortex, left posterior insula, and right insula. MDD had reduced connectivity versus controls between left posterior TPJ and right dlPFC and between right posterior TPJ and PCC and dlPFC. SZ had reduced connectivity versus MDD between right posterior TPJ and left fusiform gyrus and right superior-posterior temporal cortex. CONCLUSION: Functional connectivity to the TPJ was demonstrated to be disrupted in both SZ and MDD. However, TPJ connectivity may differ in these disorders with reduced connectivity in SZ versus MDD between TPJ and posterior brain regions.

Higher order thalamic nuclei resting network connectivity in early schizophrenia and major depressive disorder.

The pulvinar and the mediodorsal (MDN) nuclei of the thalamus are higher order nuclei which have been implicated in directed effort and corollary discharge systems. We used seed-based resting fMRI to examine functional connectivity to bilateral pulvinar and MDN in 24 schizophrenic patients (SZ), 24 major depressive disorder patients (MDD), and 24 age-matched healthy controls. SZ had less connectivity than controls between the left pulvinar and precuneus, left ventral-lateral prefrontal cortex (vlPFC), and superior and medial-frontal regions, between the right pulvinar and right frontal pole, and greater connectivity between the right MDN and left dorsolateral prefrontal cortex (dlPFC). SZ had less connectivity than MDD between the left pulvinar and ventral anterior cingulate (vACC), left vlPFC, anterior insula, posterior cingulate cortex (PCC), and right hippocampus, between the right pulvinar and right PCC, and between the right MDN and right dorsal anterior cingulate (dACC). This is the first study to measure the functional connectivity to the higher order nuclei of the thalamus in both SZ and MDD. We observed less connectivity in SZ than MDD between pulvinar and emotional encoding regions, a directed effort region, and a region involved in representation and salience, and between MDN and a directed effort region.