Detailed knowledge of the anatomy and connectivity pattern of cortico-basal ganglia circuits is essential to an understanding of abnormal cortical function and pathophysiology associated with a wide range of neurological and neuropsychiatric diseases. We aim to study the spatial extent and topography of human basal ganglia connectivity in vivo. Additionally, we explore at an anatomical level the hypothesis of coexistent segregated and integrative cortico-basal ganglia loops. We use probabilistic tractography on magnetic resonance diffusion weighted imaging data to segment basal ganglia and thalamus in 30 healthy subjects based on their cortical and subcortical projections. We introduce a novel method to define voxel-based connectivity profiles that allow representation of projections from a source to more than one target region. Using this method, we localize specific relay nuclei within predefined functional circuits. We find strong correlation between tractography-based basal ganglia parcellation and anatomical data from previously reported invasive tracing studies in nonhuman primates. Additionally, we show in vivo the anatomical basis of segregated loops and the extent of their overlap in prefrontal, premotor, and motor networks. Our findings in healthy humans support the notion that probabilistic diffusion tractography can be used to parcellate subcortical gray matter structures on the basis of their connectivity patterns. The coexistence of clearly segregated and also overlapping connections from cortical sites to basal ganglia subregions is a neuroanatomical correlate of both parallel and integrative networks within them. We believe that this method can be used to examine pathophysiological concepts in a number of basal gangliarelated disorders.

The processing of spoken language has been attributed to areas in the superior temporal lobe, where speech stimuli elicit the greatest activation. However, neurobiological and psycholinguistic models have long postulated that knowledge about the articulatory features of individual phonemes has an important role in their perception and in speech comprehension. To probe the possible involvement of specific motor circuits in the speech-perception process, we used event-related functional MRI and presented experimental subjects with spoken syllables, including [p] and [t] sounds, which are produced by movements of the lips or tongue, respectively. Physically similar nonlinguistic signal-correlated noise patterns were used as control stimuli. In localizer experiments, subjects had to silently articulate the same syllables and, in a second task, move their lips or tongue. Speech perception most strongly activated superior temporal cortex. Crucially, however, distinct motor regions in the precentral gyrus sparked by articulatory movements of the lips and tongue were also differentially activated in a somatotopic manner when subjects listened to the lip-or tongue-related phonemes. This sound-related somatotopic activation in precentral gyrus shows that, during speech perception, specific motor circuits are recruited that reflect phonetic distinctive features of the speech sounds encountered, thus providing direct neuroimaging support for specific links between the phonological mechanisms for speech perception and production.cell assembly ͉ functional MRI ͉ perception-action cycle ͉ mirror neurons ͉ phonetic distinctive featue N eurological theories of language have a long-standing tradition of distinguishing specialized modular centers for speech perception and speech production in left superior temporal and inferior frontal lobes, respectively (1-3). Such separate speech-production and -perception modules are consistent with a number of neuroimaging studies, especially the observations that frontal circuits become most strongly active during speech production and that speech input primarily activates the left superior temporal gyrus and sulcus (4-6). Superior temporal speech-perception mechanisms in humans may be situated in areas homologous to the auditory belt and parabelt areas in monkeys (5,7,8). In macaca, this region includes neurons specialized for species-specific calls (9, 10). Therefore, it appeared to be reasonable to postulate a speech-perception module confined to temporal cortex specifically processing acoustic information that is immanent to speech.In contrast to this view, neurobiological models have long claimed that speech perception is connected to production mechanisms (11-16). Similar views have been proposed in psycholinguistics. For example, the direct realist theory of speech perception (17, 18) postulates a link between motor and perceptual representations of speech. According to the motor theory of Liberman et al. (19,20), speech perception requires access to phoneme representations that are c...

Normal ageing is associated with characteristic changes in brain microstructure. Although in vivo neuroimaging captures spatial and temporal patterns of age-related changes of anatomy at the macroscopic scale, our knowledge of the underlying (patho)physiological processes at cellular and molecular levels is still limited. The aim of this study is to explore brain tissue properties in normal ageing using quantitative magnetic resonance imaging (MRI) alongside conventional morphological assessment. Using a whole-brain approach in a cohort of 26 adults, aged 18–85 years, we performed voxel-based morphometric (VBM) analysis and voxel-based quantification (VBQ) of diffusion tensor, magnetization transfer (MT), R1, and R2* relaxation parameters. We found age-related reductions in cortical and subcortical grey matter volume paralleled by changes in fractional anisotropy (FA), mean diffusivity (MD), MT and R2*. The latter were regionally specific depending on their differential sensitivity to microscopic tissue properties. VBQ of white matter revealed distinct anatomical patterns of age-related change in microstructure. Widespread and profound reduction in MT contrasted with local FA decreases paralleled by MD increases. R1 reductions and R2* increases were observed to a smaller extent in overlapping occipito-parietal white matter regions. We interpret our findings, based on current biophysical models, as a fingerprint of age-dependent brain atrophy and underlying microstructural changes in myelin, iron deposits and water. The VBQ approach we present allows for systematic unbiased exploration of the interaction between imaging parameters and extends current methods for detection of neurodegenerative processes in the brain. The demonstrated parameter-specific distribution patterns offer insights into age-related brain structure changes in vivo and provide essential baseline data for studying disease against a background of healthy ageing.

Neuroscience and clinical researchers are increasingly interested in quantitative magnetic resonance imaging (qMRI) due to its sensitivity to micro-structural properties of brain tissue such as axon, myelin, iron and water concentration. We introduce the hMRI-toolbox, an open-source, easy-to-use tool available on GitHub, for qMRI data handling and processing, presented together with a tutorial and example dataset. This toolbox allows the estimation of high-quality multi-parameter qMRI maps (longitudinal and effective transverse relaxation rates and , proton density and magnetisation transfer saturation) that can be used for quantitative parameter analysis and accurate delineation of subcortical brain structures. The qMRI maps generated by the toolbox are key input parameters for biophysical models designed to estimate tissue microstructure properties such as the MR g-ratio and to derive standard and novel MRI biomarkers. Thus, the current version of the toolbox is a first step towards in vivo histology using MRI (hMRI) and is being extended further in this direction. Embedded in the Statistical Parametric Mapping (SPM) framework, it benefits from the extensive range of established SPM tools for high-accuracy spatial registration and statistical inferences and can be readily combined with existing SPM toolboxes for estimating diffusion MRI parameter maps. From a user's perspective, the hMRI-toolbox is an efficient, robust and simple framework for investigating qMRI data in neuroscience and clinical research.

Abstract■ When speech is degraded, word report is higher for semantically coherent sentences (e.g., her new skirt was made of denim) than for anomalous sentences (e.g., her good slope was done in carrot). Such increased intelligibility is often described as resulting from "top-down" processes, reflecting an assumption that higher-level (semantic) neural processes support lower-level (perceptual) mechanisms. We used time-resolved sparse fMRI to test for top-down neural mechanisms, measuring activity while participants heard coherent and anomalous sentences presented in speech envelope/spectrum noise at varying signal-to-noise ratios (SNR). The timing of BOLD responses to more intelligible speech provides evidence of hierarchical organization, with earlier responses in peri-auditory regions of the posterior superior temporal gyrus than in more distant temporal and frontal regions. Despite Sentence content × SNR interactions in the superior temporal gyrus, prefrontal regions respond after auditory/perceptual regions. Although we cannot rule out top-down effects, this pattern is more compatible with a purely feedforward or bottom-up account, in which the results of lower-level perceptual processing are passed to inferior frontal regions. Behavioral and neural evidence that sentence content influences perception of degraded speech does not necessarily imply "top-down" neural processes. ■

Anatomical structures and mechanisms linking genes to neuropsychiatric disorders are not deciphered. Reciprocal copy number variants at the 16p11.2 BP4-BP5 locus offer a unique opportunity to study the intermediate phenotypes in carriers at high risk for autism spectrum disorder (ASD) or schizophrenia (SZ). We investigated the variation in brain anatomy in 16p11.2 deletion and duplication carriers. Beyond gene dosage effects on global brain metrics, we show that the number of genomic copies negatively correlated to the gray matter volume and white matter tissue properties in cortico-subcortical regions implicated in reward, language and social cognition. Despite the near absence of ASD or SZ diagnoses in our 16p11.2 cohort, the pattern of brain anatomy changes in carriers spatially overlaps with the well-established structural abnormalities in ASD and SZ. Using measures of peripheral mRNA levels, we confirm our genomic copy number findings. This combined molecular, neuroimaging and clinical approach, applied to larger datasets, will help interpret the relative contributions of genes to neuropsychiatric conditions by measuring their effect on local brain anatomy.

There remains much scientific, clinical, and ethical controversy concerning the use of electroconvulsive therapy (ECT) for psychiatric disorders stemming from a lack of information and knowledge about how such treatment might work, given its nonspecific and spatially unfocused nature. The mode of action of ECT has even been ascribed to a "barbaric" form of placebo effect. Here we show differential, highly specific, spatially distributed effects of ECT on regional brain structure in two populations: patients with unipolar or bipolar disorder. Unipolar and bipolar disorders respond differentially to ECT and the associated local brain-volume changes, which occur in areas previously associated with these diseases, correlate with symptom severity and the therapeutic effect. Our unique evidence shows that electrophysical therapeutic effects, although applied generally, take on regional significance through interactions with brain pathophysiology.magnetic resonance imaging | voxel-based morphometry | unipolar depression | hippocampus E lectroconvulsive therapy (ECT) is the oldest well-established procedure for somatic treatment of unipolar and bipolar disorders (1); however, its precise mechanism of action is still unclear (2). Our current understanding is that the antidepressant effect of ECT is partially mediated by seizure-induced neurotrophic effects, resulting in increased rates of neurogenesis, synaptogenesis, and glial proliferation, particularly in the hippocampus (3-5). Modern neuroimaging experiments have shown a critical role for the subgenual cortex (Brodmann area 25) (6) and deep brain stimulation of this area also results in alleviation of symptoms (7,8). Concerns regarding structural brain damage caused by ECT have been largely attenuated because of a lack of experimental evidence for ECT-induced neuronal damage (9). The scarce in vivo evidence for ECT-induced structural brain plasticity comes from region-of-interest (ROI) imaging studies reporting ECT-related hippocampal volume increases (10) that correlate with clinical outcome (11,12). Limited by an ROI approach and a lack of adequate control groups, these studies may have incompletely detected the effects of right unilateral ECT and failed to distinguish them from pharmacologically induced changes or indeed the effects of disease.We decided to resolve these ambiguities by carrying out a study with drug responsive (no-ECT) and drug-resistant (ECT) patients with either uni-or bipolar depression ( Fig. 1 and Table 1). The two psychiatric conditions are considered separate from pathophysiological and nosological viewpoints. A group of normal volunteers was included to control for non-ECT-associated confounds and to provide a way of assessing ECT-associated therapeutic effects. All subjects were recruited and imaged using structural magnetic resonance at entry (time point 1, TP1). If unresponsive to drugs, patients had ECT administered unilaterally to the right hemisphere. All study participants were imaged again at 3 mo (TP2) and 6 mo (TP3). ECT was giv...

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