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Methylphenidate (MPH) is the first choice of medical treatment for attention-deficit/hyperactivity disorder (ADHD). Its mechanism of action is to inhibit the reuptake of dopamine and noradrenaline mainly in the region of the striatum. It has been estimated that 10–30 % of patients with ADHD do not respond adequately to MPH. The aim of this study was to evaluate whether striatal differences exist between good and poor responders to MPH. The sample included 27 treatment-naïve children with ADHD between the ages of 6 and 14. MPH administration started 1 day after the MRI acquisition. After a month, psychiatrists established the good or poor response to treatment according to clinical criteria. MRI images were analyzed using a technique based on regions of interest applied specifically to the caudate and accumbens nuclei. Sixteen patients showed good response to MPH and 11 a poor one. Regions of interest analysis showed that good responders had a higher concentration of gray matter in the head of both caudate nuclei and the right nucleus accumbens. Furthermore, a significant correlation was found between caudate and accumbens nuclei volume and the Conners’ Parent Rating Scale and Continuous Performance Test improvement. These results support the hypothesis of the involvement of the caudate and accumbens nuclei in MPH response and in ADHD pathophysiology.

Decades of neuroimaging studies have shown modest differences in brain structure and connectivity in depression, hindering mechanistic insights or the identification of risk factors for disease onset 1 . Furthermore, whereas depression is episodic, few longitudinal neuroimaging studies exist, limiting understanding of mechanisms that drive mood-state transitions. The emerging field of precision functional mapping has used densely sampled longitudinal neuroimaging data to show behaviourally meaningful differences in brain network topography and connectivity between and in healthy individuals 2 – 4 , but this approach has not been applied in depression. Here, using precision functional mapping and several samples of deeply sampled individuals, we found that the frontostriatal salience network is expanded nearly twofold in the cortex of most individuals with depression. This effect was replicable in several samples and caused primarily by network border shifts, with three distinct modes of encroachment occurring in different individuals. Salience network expansion was stable over time, unaffected by mood state and detectable in children before the onset of depression later in adolescence. Longitudinal analyses of individuals scanned up to 62 times over 1.5 years identified connectivity changes in frontostriatal circuits that tracked fluctuations in specific symptoms and predicted future anhedonia symptoms. Together, these findings identify a trait-like brain network topology that may confer risk for depression and mood-state-dependent connectivity changes in frontostriatal circuits that predict the emergence and remission of depressive symptoms over time. Precision functional mapping shows that the frontostriatal salience network occupies nearly twice as much of the cortex in people with depression, and this was unaffected by mood changes and detected in children before onset of symptoms.

Parkinson's disease is characterized by abundant α-synuclein (α-Syn) neuronal inclusions, known as Lewy bodies and Lewy neurites, and the massive loss of midbrain dopamine neurons. However, a cause-and-effect relationship between Lewy inclusion formation and neurodegeneration remains unclear. Here, we found that in wild-type nontransgenic mice, a single intrastriatal inoculation of synthetic α-Syn fibrils led to the cell-to-cell transmission of pathologic α-Syn and Parkinson's-like Lewy pathology in anatomically interconnected regions. Lewy pathology accumulation resulted in progressive loss of dopamine neurons in the substantia nigra pars compacta, but not in the adjacent ventral tegmental area, and was accompanied by reduced dopamine levels culminating in motor deficits. This recapitulation of a neurodegenerative cascade thus establishes a mechanistic link between transmission of pathologic α-Syn and the cardinal features of Parkinson's disease.

Dopamine has long been thought to contribute to neurodegeneration in Parkinson's disease. The authors show that dopamine-induced neuron death in the substantia nigra is dependent on α-synuclein and coincides with increased levels of α-synuclein oligomers. The results suggest a synergistic interaction between dopamine and α-synuclein that underlies neuronal vulnerability in disease. Parkinson's disease (PD) is defined by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated both dopamine levels and α-synuclein expression. Nigrally targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine levels without damaging neurons in non-transgenic mice. In contrast, raising dopamine levels in mice expressing human A53T mutant α-synuclein induced progressive nigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53T mice increased levels of potentially toxic α-synuclein oligomers, resulting in conformationally and functionally modified species. Moreover, in genetically tractable Caenorhabditis elegans models, expression of α-synuclein mutated at the site of interaction with dopamine prevented dopamine-induced toxicity. These data suggest that a unique mechanism links two cardinal features of PD: dopaminergic cell death and α-synuclein aggregation.

The pathological hallmark of Parkinson’s disease (PD) is the formation of Lewy bodies containing aggregated alpha-synuclein (α-syn). Although PD is associated with these distinct histological changes, other pathological features such as microvascular alterations have been linked to neurodegeneration. These changes need to be investigated as they create a hostile brain microenvironment and may contribute to the development and progression of the disease. We use a human α-syn overexpression mouse model that recapitulates some of the pathological features of PD in terms of progressive aggregation of human α-syn, impaired striatal dopamine fiber density, and an age-dependent motor deficit consistent with an impaired dopamine release. We demonstrate for the first time in this model a compromised blood–brain barrier integrity and dynamic changes in vessel morphology from angiogenesis at earlier stages to vascular regression at later stages. The vascular alterations are accompanied by a pathological activation of pericytes already at an early stage without changing overall pericyte density. Our data support and further extend the occurrence of vascular pathology as an important pathophysiological aspect in PD. The model used provides a powerful tool to investigate disease-modifying factors in PD in a temporal sequence that might guide the development of new treatments.

The precise regulation of synaptic dopamine (DA) content by the dopamine transporter (DAT) ensures the phasic nature of the DA signal, which underlies the ability of DA to encode reward prediction error, thereby driving motivation, attention, and behavioral learning. Disruptions to the DA system are implicated in a number of neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD) and, more recently, Autism Spectrum Disorder (ASD). An ASD-associated de novo mutation in the SLC6A3 gene resulting in a threonine to methionine substitution at site 356 (DAT T356M) was recently identified and has been shown to drive persistent reverse transport of DA (i.e. anomalous DA efflux) in transfected cells and to drive hyperlocomotion in Drosophila melanogaster. A corresponding mutation in the leucine transporter, a DAT-homologous transporter, promotes an outward-facing transporter conformation upon substrate binding, a conformation possibly underlying anomalous dopamine efflux. Here we investigated in vivo the impact of this ASD-associated mutation on DA signaling and ASD-associated behaviors. We found that mice homozygous for this mutation display impaired striatal DA neurotransmission and altered DA-dependent behaviors that correspond with some of the behavioral phenotypes observed in ASD.

Cystathionine γ-lyase, which is responsible for the production of cysteine, is decreased in the striatum and cortex of mouse models of Huntington’s disease and in patients with Huntington’s disease, and cysteine supplementation in diet and drinking water partly rescues the phenotype and the diminished longevity of the mouse model. Cysteine link in Huntington's disease Huntington's disease is associated with polyglutamine expansion in the gene encoding huntingtin. Mutant huntingtin is expressed throughout the brain and rest of the body, but the striatum is the most affected brain region. Here it is shown that the enzyme cystathionine γ-lyase (CSE), responsible for cysteine biosynthesis, is decreased in the striatum and cortex of both mouse models and Huntington's disease patients. Mutant huntingtin inhibits the transcriptional activator Sp1, resulting in decreased CSE transcription. Cysteine supplementation in diet and drinking water partially rescues the phenotype and the diminished longevity in the mouse model, suggesting that cysteine supplementation might be beneficial for Huntington's disease patients. Huntington’s disease is an autosomal dominant disease associated with a mutation in the gene encoding huntingtin (Htt) leading to expanded polyglutamine repeats of mutant Htt (mHtt) that elicit oxidative stress, neurotoxicity, and motor and behavioural changes 1 . Huntington’s disease is characterized by highly selective and profound damage to the corpus striatum, which regulates motor function. Striatal selectivity of Huntington’s disease may reflect the striatally selective small G protein Rhes binding to mHtt and enhancing its neurotoxicity 2 . Specific molecular mechanisms by which mHtt elicits neurodegeneration have been hard to determine. Here we show a major depletion of cystathionine γ-lyase (CSE), the biosynthetic enzyme for cysteine, in Huntington’s disease tissues, which may mediate Huntington’s disease pathophysiology. The defect occurs at the transcriptional level and seems to reflect influences of mHtt on specificity protein 1, a transcriptional activator for CSE. Consistent with the notion of loss of CSE as a pathogenic mechanism, supplementation with cysteine reverses abnormalities in cultures of Huntington’s disease tissues and in intact mouse models of Huntington’s disease, suggesting therapeutic potential.

The pathological end-state of Parkinson disease is well described from postmortem tissue, but there remains a pressing need to define early functional changes to susceptible neurons and circuits. In particular, mechanisms underlying the vulnerability of the dopamine neurons of the substantia nigra pars compacta (SNc) and the importance of protein aggregation in driving the disease process remain to be determined. To better understand the sequence of events occurring in familial and sporadic Parkinson disease, we generated bacterial artificial chromosome transgenic mice (SNCA -OVX) that express wild-type α-synuclein from the complete human SNCA locus at disease-relevant levels and display a transgene expression profile that recapitulates that of endogenous α-synuclein. SNCA -OVX mice display age-dependent loss of nigrostriatal dopamine neurons and motor impairments characteristic of Parkinson disease. This phenotype is preceded by early deficits in dopamine release from terminals in the dorsal, but not ventral, striatum. Such neurotransmission deficits are not seen at either noradrenergic or serotoninergic terminals. Dopamine release deficits are associated with an altered distribution of vesicles in dopaminergic axons in the dorsal striatum. Aged SNCA -OVX mice exhibit reduced firing of SNc dopamine neurons in vivo measured by juxtacellular recording of neurochemically identified neurons. These progressive changes in vulnerable SNc neurons were observed independently of overt protein aggregation, suggesting neurophysiological changes precede, and are not driven by, aggregate formation. This longitudinal phenotyping strategy in SNCA -OVX mice thus provides insights into the region-specific neuronal disturbances preceding and accompanying Parkinson disease.

Catatonia is a nosologically unspecific syndrome, which subsumes a plethora of mostly complex affective, motor, and behavioral phenomena. Although catatonia frequently occurs in schizophrenia spectrum disorders (SSD), specific patterns of abnormal brain structure and function underlying catatonia are unclear at present. Here, we used a multivariate data fusion technique for multimodal magnetic resonance imaging (MRI) data to investigate patterns of aberrant intrinsic neural activity (INA) and gray matter volume (GMV) in SSD patients with and without catatonia. Resting-state functional MRI and structural MRI data were collected from 87 right-handed SSD patients. Catatonic symptoms were examined on the Northoff Catatonia Rating Scale (NCRS). A multivariate analysis approach was used to examine co-altered patterns of INA and GMV. Following a categorical approach, we found predominantly frontothalamic and corticostriatal abnormalities in SSD patients with catatonia (NCRS total score ≥ 3; n = 24) when compared to SSD patients without catatonia (NCRS total score = 0; n = 22) matched for age, gender, education, and medication. Corticostriatal network was associated with NCRS affective scores. Following a dimensional approach, 33 SSD patients with catatonia according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision were identified. NCRS behavioral scores were associated with a joint structural and functional system that predominantly included cerebellar and prefrontal/cortical motor regions. NCRS affective scores were associated with frontoparietal INA. This study provides novel neuromechanistic insights into catatonia in SSD suggesting co-altered structure/function-interactions in neural systems subserving coordinated visuospatial functions and motor behavior.

Alterations in regional subcortical brain volumes have been investigated as part of the efforts of an international consortium, ENIGMA, to identify reliable neural correlates of major depressive disorder (MDD). Given that subcortical structures are comprised of distinct subfields, we sought to build significantly from prior work by precisely mapping localized MDD‐related differences in subcortical regions using shape analysis. In this meta‐analysis of subcortical shape from the ENIGMA‐MDD working group, we compared 1,781 patients with MDD and 2,953 healthy controls (CTL) on individual measures of shape metrics (thickness and surface area) on the surface of seven bilateral subcortical structures: nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Harmonized data processing and statistical analyses were conducted locally at each site, and findings were aggregated by meta‐analysis. Relative to CTL, patients with adolescent‐onset MDD (≤ 21 years) had lower thickness and surface area of the subiculum, cornu ammonis (CA) 1 of the hippocampus and basolateral amygdala (Cohen's d = −0.164 to −0.180). Relative to first‐episode MDD, recurrent MDD patients had lower thickness and surface area in the CA1 of the hippocampus and the basolateral amygdala (Cohen's d = −0.173 to −0.184). Our results suggest that previously reported MDD‐associated volumetric differences may be localized to specific subfields of these structures that have been shown to be sensitive to the effects of stress, with important implications for mapping treatments to patients based on specific neural targets and key clinical features.