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Journal of Psychiatry & Neuroscience :... Apr 2021Major depressive disorder (MDD) is characterized by impaired cortical-subcortical functional connectivity. Apathy adds to functional impairment, but its cerebral basis...
BACKGROUND
Major depressive disorder (MDD) is characterized by impaired cortical-subcortical functional connectivity. Apathy adds to functional impairment, but its cerebral basis in MDD remains unknown. Our objective was to describe impairments in functional connectivity during emotional processing in MDD (with varying levels of congruency and attention), and to determine their correlation with apathy.
METHODS
We used the Variable Attention Affective Task during functional MRI, followed by diffusion-weighted MRI, to assess 55 right-handed women (30 with MDD and 25 healthy controls) between September 2012 and February 2015. We estimated functional connectivity using generalized psychophysiologic interaction and anatomic connectivity with tract-based spatial statistics. We measured apathy using the Apathy Evaluation Scale.
RESULTS
We found decreased functional connectivity between the left amygdala and the left anterior cingulate cortex (ACC) during negative stimuli in participants with MDD (t54 = 4.2; p = 0.035, family-wise error [FWE]-corrected). During high-attention stimuli, participants with MDD showed reduced functional connectivity between the right dorsolateral prefrontal cortex (dlPFC) and the right ACC (t54 = 4.06, pFWE = 0.02), but greater functional connectivity between the right dlPFC and the right amygdala (t54 = 3.35, p = 0.048). Apathy was associated with increased functional connectivity between the right dlPFC and the right ACC during high-attention stimuli (t28 = 5.2, p = 0.01) and increased fractional anisotropy in the right posterior cerebellum, the anterior and posterior cingulum and the bilateral internal capsule (all pFWE < 0.05).
LIMITATIONS
Limitations included a moderate sample size, concomitant antidepressant therapy and no directed connectivity.
CONCLUSION
We found that MDD was associated with impairments in cortical-subcortical functional connectivity during negative stimuli that might alter the recruitment of networks engaged in attention. Apathy-related features suggested networks similar to those observed in degenerative disorders, but possible different mechanisms.
Topics: Brain; Depressive Disorder, Major; Dorsolateral Prefrontal Cortex; Emotions; Female; Humans; Magnetic Resonance Imaging; Middle Aged; Motivation; Multimodal Imaging; Neuroimaging
PubMed: 33844485
DOI: 10.1503/jpn.200074 -
Scientific Reports Jul 2016The striatum controls multiple cognitive aspects including motivation, reward perception, decision-making and motor planning. In particular, the dorsolateral striatum...
The striatum controls multiple cognitive aspects including motivation, reward perception, decision-making and motor planning. In particular, the dorsolateral striatum contributes to motor learning. Here we define an approach for investigating synaptic plasticity in mouse dorsolateral cortico-striatal circuitry and interrogate the relative contributions of neurotransmitter receptors and intracellular signaling components. Consistent with previous studies, we show that long-term potentiation (LTP) in cortico-striatal circuitry is facilitated by dopamine, and requires activation of D1-dopamine receptors, as well as NMDA receptors (NMDAR) and their calcium-dependent downstream effectors, including CaMKII. Moreover, we assessed the contribution of the protein kinase Cdk5, a key neuronal signaling molecule, in cortico-striatal LTP. Pharmacological Cdk5 inhibition, brain-wide Cdk5 conditional knockout, or viral-mediated dorsolateral striatal-specific loss of Cdk5 all impaired dopamine-facilitated LTP or D1-dopamine receptor-facilitated LTP. Selective loss of Cdk5 in dorsolateral striatum increased locomotor activity and attenuated motor learning. Taken together, we report an approach for studying synaptic plasticity in mouse dorsolateral striatum and critically implicate D1-dopamine receptor, NMDAR, Cdk5, and CaMKII in cortico-striatal plasticity. Furthermore, we associate striatal plasticity deficits with effects upon behaviors mediated by this circuitry. This approach should prove useful for the study of the molecular basis of plasticity in the dorsolateral striatum.
Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Corpus Striatum; Cyclin-Dependent Kinase 5; Dopamine; Learning; Locomotion; Long-Term Potentiation; Male; Mice; Receptors, Dopamine D1; Receptors, N-Methyl-D-Aspartate; Synaptic Transmission
PubMed: 27443506
DOI: 10.1038/srep29812 -
PloS One 2018Mormyrid fish rely on reafferent input for active electrolocation. Their electrosensory input consists of phase and amplitude information. These are encoded by...
Mormyrid fish rely on reafferent input for active electrolocation. Their electrosensory input consists of phase and amplitude information. These are encoded by differently tuned receptor cells within the Mormyromasts, A- and B-cells, respectively, which are distributed over the animal's body. These convey their information to two topographically ordered medullary zones in the electrosensory lateral line lobe (ELL). The so-called medial zone receives only amplitude information, while the dorsolateral zone receives amplitude and phase information. Using both sources of information, Mormyrid fish can disambiguate electrical impedances. Where and how this disambiguation takes place is presently unclear. We here investigate phase-sensitivity downstream from the electroreceptors. We provide first evidence of phase-sensitivity in the medial zone of ELL. In this zone I-cells consistently decreased their rate to positive phase-shifts (6 of 20 cells) and increased their rate to negative shifts (11/20), while E-cells of the medial zone (3/9) responded oppositely to I-cells. In the dorsolateral zone the responses of E- and I-cells were opposite to those found in the medial zone. Tracer injections revealed interzonal projections that interconnect the dorsolateral and medial zones in a somatotopic manner. In summary, we show that phase information is processed differently in the dorsolateral and the medial zones. This is the first evidence for a mechanism that enhances the contrast between two parallel sensory channels in Mormyrid fish. This could be beneficial for impedance discrimination that ultimately must rely on a subtractive merging of these two sensory streams.
Topics: Animals; Electric Fish; Electric Organ; Electrophysiological Phenomena; Fishes; Neurons; Sensation; Sensory Receptor Cells
PubMed: 29641541
DOI: 10.1371/journal.pone.0194347 -
Schizophrenia Research May 2022Clozapine (CLZ) demonstrates a unique clinical efficacy relative to other antipsychotic drugs. Previous work has linked the plasma ratio of CLZ and its major metabolite,...
Clozapine (CLZ) demonstrates a unique clinical efficacy relative to other antipsychotic drugs. Previous work has linked the plasma ratio of CLZ and its major metabolite, N-desmethylclozapine (NDMC), to an inverse relationship with cognition via putative action on the cholinergic system. However, neuroimaging correlates of CLZ/NDMC remain unknown. Here, we examined changes in basal forebrain functional connectivity with the dorsolateral prefrontal cortex, and secondly, cognition in relation to the CLZ/NDMC ratio. A cohort of nineteen chronically ill participants with treatment-resistant schizophrenia (TRS) undergoing 12 weeks of CLZ treatment were included. Measures of cognition and plasma CLZ/NDMC ratios were obtained in addition to resting-state functional neuroimaging scans, captured at baseline and after 12 weeks of CLZ treatment. We observed a significant correlation between basal forebrain-DLPFC connectivity and CLZ/NDMC ratios across CLZ treatment (p = 0.02). Consistent with previous findings, we also demonstrate a positive relationship between CLZ/NDMC ratio and working memory (p = 0.03). These findings may reflect the action of CLZ and NDMC on the muscarinic cholinergic system, highlighting a possible neural correlate of cognition across treatment.
Topics: Antipsychotic Agents; Basal Forebrain; Cholinergic Agents; Clozapine; Dorsolateral Prefrontal Cortex; Humans; Schizophrenia; Schizophrenia, Treatment-Resistant
PubMed: 35381515
DOI: 10.1016/j.schres.2022.03.014 -
JAMA Psychiatry May 2024The risk of mental disorders is consistently associated with variants in CACNA1C (L-type calcium channel Cav1.2) but it is not known why these channels are critical to...
IMPORTANCE
The risk of mental disorders is consistently associated with variants in CACNA1C (L-type calcium channel Cav1.2) but it is not known why these channels are critical to cognition, and whether they affect the layer III pyramidal cells in the dorsolateral prefrontal cortex that are especially vulnerable in cognitive disorders.
OBJECTIVE
To examine the molecular mechanisms expressed in layer III pyramidal cells in primate dorsolateral prefrontal cortices.
DESIGN, SETTING, AND PARTICIPANTS
The design included transcriptomic analyses from human and macaque dorsolateral prefrontal cortex, and connectivity, protein expression, physiology, and cognitive behavior in macaques. The research was performed in academic laboratories at Yale, Harvard, Princeton, and the University of Pittsburgh. As dorsolateral prefrontal cortex only exists in primates, the work evaluated humans and macaques.
MAIN OUTCOMES AND MEASURES
Outcome measures included transcriptomic signatures of human and macaque pyramidal cells, protein expression and interactions in layer III macaque pyramidal cells using light and electron microscopy, changes in neuronal firing during spatial working memory, and working memory performance following pharmacological treatments.
RESULTS
Layer III pyramidal cells in dorsolateral prefrontal cortex coexpress a constellation of calcium-related proteins, delineated by CALB1 (calbindin), and high levels of CACNA1C (Cav1.2), GRIN2B (NMDA receptor GluN2B), and KCNN3 (SK3 potassium channel), concentrated in dendritic spines near the calcium-storing smooth endoplasmic reticulum. L-type calcium channels influenced neuronal firing needed for working memory, where either blockade or increased drive by β1-adrenoceptors, reduced neuronal firing by a mean (SD) 37.3% (5.5%) or 40% (6.3%), respectively, the latter via SK potassium channel opening. An L-type calcium channel blocker or β1-adrenoceptor antagonist protected working memory from stress.
CONCLUSIONS AND RELEVANCE
The layer III pyramidal cells in the dorsolateral prefrontal cortex especially vulnerable in cognitive disorders differentially express calbindin and a constellation of calcium-related proteins including L-type calcium channels Cav1.2 (CACNA1C), GluN2B-NMDA receptors (GRIN2B), and SK3 potassium channels (KCNN3), which influence memory-related neuronal firing. The finding that either inadequate or excessive L-type calcium channel activation reduced neuronal firing explains why either loss- or gain-of-function variants in CACNA1C were associated with increased risk of cognitive disorders. The selective expression of calbindin in these pyramidal cells highlights the importance of regulatory mechanisms in neurons with high calcium signaling, consistent with Alzheimer tau pathology emerging when calbindin is lost with age and/or inflammation.
PubMed: 38776078
DOI: 10.1001/jamapsychiatry.2024.1112 -
International Journal of Clinical and... 2020Activation likelihood estimation meta-analysis was performed to examine the activation characteristics of cognition-related brain regions in patients with mild traumatic... (Review)
Review
Activation likelihood estimation meta-analysis was performed to examine the activation characteristics of cognition-related brain regions in patients with mild traumatic brain injury (mTBI). The databases PubMed, Ovid, Cochrane Library, Google Scholar, CNKI, WFSD, and VIP were systematically searched. The software Ginger-ALE 3.0.2 was used for coordinate unification and meta-analysis. Seven studies with a total of 314 subjects were included. Meta-analysis results indicated that compared with healthy subjects, mTBI patients had enhanced activation in the left anterior angular gyrus, left occipital joint visual, left midbrain, right temporal angular gyrus, right cerebellar tonsil, left frontal insula, and right inferior frontal gyrus. mTBI patients had attenuated activation in the right dorsolateral prefrontal lobe, left cerebellar anterior lobe, left dorsolateral prefrontal lobe, right middle frontal gyrus, right posterior cingulate gyrus, left joint visual, left supramarginal gyrus, left middle frontal gyrus, right precuneus, left dorsolateral prefrontal cortex, right frontal eye field, right lower parietal gyrus, corpus callosum, right frontal pole region, and left prefrontal lobe. Further joint analysis revealed that the dorsolateral prefrontal lobe of the right middle frontal gyrus was a region of attenuated co-activation. The dorsolateral prefrontal lobe of the right middle frontal gyrus showing attenuated activation was the main brain region distinguishing mTBI patients from healthy subjects. Cognitive deficits could be associated with attenuated activation in the dorsolateral prefrontal lobe of the right middle frontal gyrus, which could be due to a decline in the recruitment ability of the neural network involved in controlling attention.
PubMed: 33425093
DOI: No ID Found -
Neuropsychiatric Disease and Treatment 2021Previous studies suggested a link between serotonergic neurotransmission and impaired insight in schizophrenia. In this study, we examined the relationship between...
Association Between Lack of Insight and Prefrontal Serotonin Transporter Availability in Antipsychotic-Free Patients with Schizophrenia: A High-Resolution PET Study with [C]DASB.
BACKGROUND
Previous studies suggested a link between serotonergic neurotransmission and impaired insight in schizophrenia. In this study, we examined the relationship between serotonin transporter (SERT) availability in regions of the prefrontal cortex (dorsolateral, ventrolateral, ventromedial, and orbitofrontal cortices) and insight deficits in antipsychotic-free patients with schizophrenia using high-resolution positron emission tomography (PET) with [C]DASB.
METHODS
Nineteen patients underwent [C]DASB PET and 7-Tesla magnetic resonance imaging scans. To assess SERT availability, the binding potential with respect to non-displaceable compartment (BP) was derived using the simplified reference tissue model. Patients' level of insight was assessed using the Insight and Treatment Attitude Questionnaire (ITAQ). The relationship between ITAQ scores and [C]DASB BP values was examined using the region-of-interest (ROI)- and voxel-based analyses with relevant variables as covariates. The prefrontal cortex and its four subregions were selected as a priori ROIs since the prefrontal cortex has been implicated as the critical neuroanatomical substrate of impaired insight in schizophrenia.
RESULTS
The ROI-based analysis revealed that the ITAQ illness insight dimension had significant negative correlations with the [C]DASB BP in the left dorsolateral, left orbitofrontal, and bilateral ventrolateral prefrontal cortices. The ITAQ treatment insight dimension had significant negative correlations with the [C]DASB BP in the bilateral dorsolateral, left orbitofrontal, and bilateral ventrolateral prefrontal cortices. The ITAQ total score showed significant negative correlations with the [C]DASB BP in the bilateral prefrontal cortex and three subregions (dorsolateral, ventrolateral, and orbitofrontal cortices). A supplementary voxel-based analysis corroborated a significant negative association between the ITAQ score and the [C]DASB BP in the prefrontal cortices.
CONCLUSION
Our study provides in vivo evidence of significant negative correlations between insight deficits and prefrontal SERT availability in patients with schizophrenia, suggesting significant involvement of prefrontal serotonergic signaling in impaired insight, one of the core symptoms of schizophrenia.
PubMed: 34707358
DOI: 10.2147/NDT.S336126 -
In Vivo (Athens, Greece) 2022Lesions in the seminal vesicle are described in the most used protocols for prostate cancer (PCa) induction. This study aimed to characterize the lesions of seminal...
BACKGROUND/AIM
Lesions in the seminal vesicle are described in the most used protocols for prostate cancer (PCa) induction. This study aimed to characterize the lesions of seminal vesicles associated with a protocol of PCa induction in rats to contribute to better characterization of this model.
MATERIALS AND METHODS
Forty-five male Wistar Unilever rats were randomly divided into two control groups: CONT1 (n=10) and CONT2 (n=10); and two PCa-induced groups: IND1 (n=10) and IND2 (n=15), sacrificed at 35 and 61 weeks, respectively. Animals from the induced groups were exposed to a multistep protocol for PCa induction. Animals, seminal vesicles and dorsolateral prostate were weighed. Seminal vesicles and dorsolateral prostate were submitted to histopathological and immunohistochemical analysis.
RESULTS
Animals in which PCa was induced had a lower mean body weight when compared with the control animals (p<0.05). The relative mean seminal vesicle weight was higher in groups with PCa when compared with control groups (p<0.05). Although the differences were not statistically significant, animals from the IND2 group developed more lesions than animals from the IND1 and CONT2 groups. It is worth noting that the animals from group IND2 developed papillary adenomas and carcinomas in situ, which were not observed in any other group. Similar to observations in seminal vesicles, animals from group IND2 developed more dorsolateral prostate lesions than animals from the IND1 group (p<0.05).
CONCLUSION
We observed that the longer the exposure to testosterone was, the greater was the incidence of preneoplastic and neoplastic lesions in both the seminal vesicle and the prostate, suggesting that testosterone exposure affects the spectrum of developed lesions.
Topics: Humans; Rats; Male; Animals; Seminal Vesicles; Prostate; Rats, Wistar; Prostatic Neoplasms; Testosterone
PubMed: 36309374
DOI: 10.21873/invivo.13001 -
The Journal of Physiology Aug 2018There are two electrophysiological dichotomous populations of parvalbumin (PV) interneurons located in the dorsal striatum. Striatal PV interneurons in medial and...
KEY POINTS
There are two electrophysiological dichotomous populations of parvalbumin (PV) interneurons located in the dorsal striatum. Striatal PV interneurons in medial and lateral regions differ significantly in their intrinsic excitability. Parvalbumin interneurons in the dorsomedial striatum, but not in the dorsolateral striatum, receive afferent glutamatergic input from cingulate cortex.
ABSTRACT
Dorsomedial striatum circuitry is involved in goal-directed actions or movements that become habits upon repetition, as encoded by the dorsolateral striatum. An inability to shift from habits can compromise action-control and prevent behavioural adaptation. Although these regions appear to be clearly behaviourally distinct, little is known about their distinct physiology. Parvalbumin (PV) interneurons are a major source of striatal inhibition and are usually considered as a homogeneous population in the entire dorsal striatum. In the present study, we recorded PV interneurons in dorsal striatum slices from wild-type male mice and suggest the existence of two electrophysiological dichotomous populations. We found that PV interneurons located at the dorsomedial striatum region have increased intrinsic excitability compared to PV interneurons in dorsolateral region. We also found that PV interneurons in the dorsomedial region, but not in the dorsolateral striatum region, receive short-latency excitatory inputs from cingulate cortex. Therefore, the results of the present study demonstrate the importance of considering region specific parvalbumin interneuron populations when studying dorsal striatal function.
Topics: Afferent Pathways; Animals; Corpus Striatum; Functional Laterality; Glutamic Acid; Interneurons; Male; Mice; Mice, Knockout; Parvalbumins
PubMed: 29808928
DOI: 10.1113/JP275936 -
Medicine Feb 2024Lateral medullary syndrome is caused by atherosclerosis or embolism of the vertebral artery and its branches or the posterior inferior cerebellar artery (PICA).The...
RATIONALE
Lateral medullary syndrome is caused by atherosclerosis or embolism of the vertebral artery and its branches or the posterior inferior cerebellar artery (PICA).The eight-and-a-half syndrome is a rare pontocerebellar nerve-ocular syndrome presenting as a one-and-a-half syndrome plus ipsilateral seventh cerebral nerve palsy. The dorsolateral medullary syndrome combined with the eight-and-a-half syndromes is even rarer, so it is important to recognize the features of the classical brainstem syndrome and the eight-and-a-half syndromes.
PATIENT CONCERNS
Most patients with dorsolateral medullary syndrome combined with eight-and-a-half syndromes have a good prognosis, with recovery occurring within a few weeks to a few months, although a few patients may take longer to recover.
DIAGNOSIS INTERVENTIONS
In the course of disease development, the patient developed dysarthria, dysphagia, hypothermia, ipsilateral Horner sign and ataxia. Computed tomography was performed which showed cerebral infarction in the left brainstem. Cranial diffusion-weighted imaging + magnetic resonance angiography showed acute infarction in the left cerebellar hemisphere, with a high probability of severe stenosis or occlusion in the intracranial and proximal segments of the basilar arteries. This supports the diagnosis of dorsolateral medullary syndrome. The patient's limited adduction and abduction of the left eye and limited adduction of the right eye, combined with peripheral paralysis of the affected lateral nerve, supported the diagnosis of eight-and-a-half syndromes. The administration of antiplatelet and anti-ester fixation treatment can effectively improve the symptoms and shorten the course of the disease.
OUTCOMES
After antiplatelet and anti-ester fixation treatment, the symptoms improved and the patient was discharged.
LESSONS
Dorsolateral medullary syndrome combined with eight-and-a-half syndromes is a rare clinical condition, and therefore more attention should be paid to the early diagnosis and treatment of such patients.
Topics: Humans; Lateral Medullary Syndrome; Cerebellum; Cerebral Infarction; Infarction; Vertebral Artery; Facial Paralysis
PubMed: 38335410
DOI: 10.1097/MD.0000000000034409