Preferential networks of the mediodorsal nucleus and centromedian-parafascicular complex of the thalamus-A DTI tractography study

Distinct thalamic nuclei, like the mediodorsal (MD) nucleus and the centromedian/parafascicular complex (CM/Pf), are embedded in different basal ganglia—thalamocortical loops, which were shown to integrate cognitive and emotional aspects of human behavior. Despite well described connections on a microscopic scale, derived from tracing studies in animals, little is known about the intrinsic anatomical connections of these nuclei in humans. This lack of knowledge limits not only interpretation of functional imaging studies but also estimation of direct effects of deep brain stimulation which treats diseases as different as epilepsy or major depression. Therefore, non‐invasive diffusion tensor imaging (DTI) studies are key to analyzing connectivity patterns and elaborate approaches to close this gap. For our study, we explored the structural connectivity of the MD thalamic nuclei and the CM/Pf complex towards five cortical and six subcortical regions by using a preferential fiber calculation. We found both thalamic nuclei to be preferentially associated to distinct networks: whereas the MD is preferentially connected to prefrontal and limbic cortical regions, the CM is linked to subcortical regions. The anterior insula was the only cortical region associated with the subcortical network of the CM and the cortical network of the MD comprised one subcortical hub, the caudate nucleus, suggesting an integrative role of these two regions. Adding to predescribed anatomical tract tracing connectivities in animal studies, our finding lends support to the existence of similar basal ganglia‐thalamocortical circuits in humans and we could show a robust distinction of preferential connectivity for both thalamic nuclei. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

Organisation of the reticular thalamic projection to the intralaminar and midline nuclei in rats

This study examines the projection of the reticular thalamic nucleus to the classic “nonspecific” dorsal thalamic nuclei of rats. Individual nuclei of the intralaminar (central-lateral, paracentral, central-medial, parafascicular) and the midline (reuniens/rhomboid, parataenial) nuclear groups, together with the reticular nucleus itself, were injected with the neuronal tracers biotinylated dextran or fluorescent latex microspheres (red or green). Reticular cells projecting to the intralaminar and midline nuclei are limited largely to the rostral pole of the nucleus. Within the rostral pole, most reticular cells projecting to the intralaminar and midline nuclear groups are found in largely distinct sectors; cells that project to the intralaminar nuclei tend to lie more laterally, whereas those projecting to the midline nuclei lie more medially within the pole. Among the individual nuclei of both the intralaminar and midline nuclear groups, however, the segregation is far less distinct. For instance, the reticular cells that project to the intralaminar central-lateral, central-medial, paracentral, and parafascicular nuclei are intermixed completely on the lateral edge of the rostral pole. After separate injections of different colored latex microspheres into individual intralaminar nuclei, the incidence of double-labelled reticular cells is about 37%, a percentage much higher than among the “specific” dorsal thalamic nuclei (<1%). All the above-mentioned results refer to the reticular labelling seen on the side ipsilateral to the injection. After separate injections into the intralaminar central-medial nucleus, the midline nuclei, and the reticular nucleus itself, we also see a very small group of reticular cells labelled on the contralateral side. In general, our results indicate that the reticular projection to the intralaminar and midline nuclei is far more diffuse than the reticular projection to the specific dorsal thalamic nuclei. J. Comp. Neurol. 377:165–178, 1997. © 1997 Wiley-Liss, Inc.     

Neuropsychiatric symptoms in Alzheimer's disease are related to functional connectivity alterations in the salience network

Neuropsychiatric syndromes are highly prevalent in Alzheimer's disease (AD), but their neurobiology is not completely understood. New methods in functional magnetic resonance imaging, such as intrinsic functional connectivity or “resting‐state” analysis, may help to clarify this issue. Using such approaches, alterations in the default‐mode and salience networks (SNs) have been described in Alzheimer's, although their relationship with specific symptoms remains unclear. We therefore carried out resting‐state functional connectivity analysis with 20 patients with mild to moderate AD, and correlated their scores on neuropsychiatric inventory syndromes (apathy, hyperactivity, affective syndrome, and psychosis) with maps of connectivity in the default mode network and SN. In addition, we compared network connectivity in these patients with that in 17 healthy elderly control subjects. All analyses were controlled for gray matter density and other potential confounds. Alzheimer's patients showed increased functional connectivity within the SN compared with controls (right anterior cingulate cortex and left medial frontal gyrus), along with reduced functional connectivity in the default‐mode network (bilateral precuneus). A correlation between increased connectivity in anterior cingulate cortex and right insula areas of the SN and hyperactivity syndrome (agitation, irritability, aberrant motor behavior, euphoria, and disinhibition) was found. These findings demonstrate an association between specific network changes in AD and particular neuropsychiatric symptom types. This underlines the potential clinical significance of resting state alterations in future diagnosis and therapy. Hum Brain Mapp 35:1237–1246, 2014. © 2013 Wiley Periodicals, Inc.     

Aging effects on the resting state motor network and interlimb coordination

Both increases and decreases in resting state functional connectivity have been previously observed within the motor network during aging. Moreover, the relationship between altered functional connectivity and age‐related declines in bimanual coordination remains unclear. Here, we explored the developmental dynamics of the resting brain within a task‐specific motor network in a sample of 128 healthy participants, aged 18–80 years. We found that age‐related increases in functional connectivity between interhemispheric dorsal and ventral premotor areas were associated with poorer performance on a novel bimanual visuomotor task. Additionally, a control analysis performed on the default mode network confirmed that our age‐related increases in functional connectivity were specific to the motor system. Our findings suggest that increases in functional connectivity within the resting state motor network with aging reflect a loss of functional specialization that may not only occur in the active brain but also in the resting brain. Hum Brain Mapp 35:3945–3961, 2014. © 2014 Wiley Periodicals, Inc .     

The thalamostriatal system: a highly specific network of the basal ganglia circuitry

Although the existence of thalamostriatal projections has long been known, the role(s) of this system in the basal ganglia circuitry remains poorly characterized. The intralaminar and ventral motor nuclei are the main sources of thalamic inputs to the striatum. This review emphasizes the high degree of anatomical and functional specificity of basal ganglia-thalamostriatal projections and discusses various aspects of the synaptic connectivity and neurochemical features that differentiate this glutamate system from the corticostriatal network. It also discusses the importance of thalamostriatal projections from the caudal intralaminar nuclei in the process of attentional orientation. A major task of future studies is to characterize the role(s) of corticostriatal and thalamostriatal pathways in regulating basal ganglia activity in normal and pathological conditions.     

Resting state connectivity of the bed nucleus of the stria terminalis at ultra‐high field

The bed nucleus of the stria terminalis (BNST), a portion of the “extended amygdala,” is implicated in the pathophysiology of anxiety and addiction disorders. Its small size and connection to other small regions prevents standard imaging techniques from easily capturing it and its connectivity with confidence. Seed‐based resting state functional connectivity is an established method for mapping functional connections across the brain from a region of interest. We, therefore, mapped the BNST resting state network with high spatial resolution using 7 Tesla fMRI, demonstrating the in vivo reproduction of many human BNST connections previously described only in animal research. We identify strong BNST functional connectivity in amygdala, hippocampus and thalamic subregions, caudate, periaqueductal gray, hypothalamus, and cortical areas such as the medial PFC and precuneus. This work, which demonstrates the power of ultra‐high field for mapping functional connections in the human, is an important step toward elucidating cortical and subcortical regions and subregions of the BNST network. Hum Brain Mapp 36:4076–4088, 2015. © 2015 Wiley Periodicals, Inc.     

Basal ganglia involvement in memory-guided movement sequencing

The basal ganglia (BG) are thought to play a critical role in motor planning and movement sequencing. While electrophysiological and imaging studies have shown that the dorso-lateral prefrontal cortex (DLPFC) is involved in working memory (WM), the involvement of the BG in this process is not well understood. We used a motor sequencing task to investigate the differential role of BG nuclei in memory-guided movement. Significant activation was observed in the DLPFC and posterior putamen and globus pallidus (GP), with a trend in the caudate and no differences in the anterior putamen. We then investigated the effect of BG outflow on thalamic activation using functional connectivity analysis. Activation in the posterior putamen + GP was found to be correlated with thalamic activation only in the hemisphere contralateral to movement. These results provide the first fMRI evidence that the BG may modulate activity in the thalamus during working memory-guided movement sequencing. Our findings suggest that the BG activation may reflect increased motor sequencing demands during the memory-guided movement condition and, specifically, that the posterior putamen and GP may play a role in maintenance of representations in WM in a manner that contributes to planning and temporal organization of motor sequencing.     

Blood oxygenation level–dependent activation in basal ganglia nuclei relates to specific symptoms in de novo Parkinson's disease

To aid the development of symptomatic and disease modifying therapies in Parkinson's disease (PD), there is a strong need to identify noninvasive measures of basal ganglia (BG) function that are sensitive to disease severity. This study examines the relation between blood oxygenation level–dependent (BOLD) activation in every nucleus of the BG and symptom‐specific disease severity in early stage de novo PD. BOLD activation measured at 3 T was compared between 20 early stage de novo PD patients and 20 controls during an established precision grip force task. In addition to the BG nuclei, activation in specific thalamic and cortical regions was examined. There were three novel findings. First, there were significant negative correlations between total motor Unified PD Rating Scale and BOLD activation in bilateral caudate, bilateral putamen, contralateral external segment of the globus pallidus, bilateral subthalamic nucleus, contralateral substantia nigra, and thalamus. Second, bradykinesia was the symptom that most consistently predicted BOLD activation in the BG and thalamus. Also, BOLD activation in the contralateral internal globus pallidus was related to tremor. Third, the reduced cortical activity in primary motor cortex and supplementary motor area in de novo PD did not relate to motor symptoms. These findings demonstrate that BOLD activity in nuclei of the BG relates most consistently to bradykinesia and functional magnetic resonance imaging has strong potential to serve as a noninvasive marker for the state of BG function in de novo PD. © 2010 Movement Disorder Society     

Network abnormalities among non‐manifesting Parkinson disease related LRRK2 mutation carriers

Non‐manifesting carriers (NMC) of the G2019S mutation in the LRRK2 gene represent an “at risk” group for future development of Parkinson's disease (PD) and have demonstrated task related fMRI changes. However, resting‐state networks have received less research focus, thus this study aimed to assess the integrity of the motor, default mode (DMN), salience (SAL), and dorsal attention (DAN) networks among this unique population by using two different connectivity measures: interregional functional connectivity analysis and Dependency network analysis (D_EPNA). Machine learning classification methods were used to distinguish connectivity between the two groups of participants. Forty‐four NMC and 41 non‐manifesting non‐carriers (NMNC) participated in this study; while no behavioral differences on standard questionnaires could be detected, NMC demonstrated lower connectivity measures in the DMN, SAL, and DAN compared to NMNC but not in the motor network. Significant correlations between NMC connectivity measures in the SAL and attention were identified. Machine learning classification separated NMC from NMNC with an accuracy rate above 0.8. Reduced integrity of non‐motor networks was detected among NMC of the G2019S mutation in the LRRK2 gene prior to identifiable changes in connectivity of the motor network, indicating significant non‐motor cerebral changes among populations “at risk” for future development of PD.     

Organization of thalamic projections in the nucleus accumbens and the caudate nucleus in cats and its relation with hippocampal and other subcortical afferents

The organization of thalamic projections in the nucleus accumbens (NA) and the caudate nucleus of cats and its relation to other subcortical striatal afferents were studied with a retrograde tracing technique by use of lectin-conjugated horseradish peroxidase. The study showed that the paraventricular and medial parafascicular nuclei (PF) of the thalamus project to the medial NA and the parataenial and medial PF project to the lateral NA. The ventral tegmental area and substantia nigra pars dorsalis (SNpd) project to medial and lateral NA. The midline thalamic nuclei, rostral intralaminar nuclei, ventroanterior nucleus, medial and lateral PF, lateral posterior complex, and nucleus limitans project to medial caudate nucleus. The most medial substantia nigra pars compacta (SNpc) and rostral SNpd project to medial caudate nucleus. The center median, ventrolateral, and the central lateral nuclei of thalamus, SNpc, and SNpd project to lateral caudate nucleus. These results suggest that the thalamic and subcortical nuclei known to connect with the limbic and frontal cortices project to NA and medial caudate nucleus. Those thalamic nuclei connected with the motor system project to lateral caudate nucleus. The hippocampus projects selectively to medial NA. The amygdala, raphe, and other mesencephalic nuclei project only to NA and medial caudate nucleus. The organization of hippocampal, amygdala, and other subcortical afferents suggests that NA and caudate nucleus can be separated into medial "limbic" and lateral nonlimbic "sensory-motor" compartments. A brief review of the distribution pattern of some neurotransmitters, neuropeptides, and their receptors and behavior studies provides additional support to the concept that the striatum can be divided into several subcompartments.     

The role of anterior midcingulate cortex in cognitive motor control

The rostral cingulate cortex has been associated with a multitude of cognitive control functions. Recent neuroimaging data suggest that the anterior midcingulate cortex (aMCC) has a key role for cognitive aspects of movement generation, i.e., intentional motor control. We here tested the functional connectivity of this area using two complementary approaches: (1) resting‐state connectivity of the aMCC based on fMRI scans obtained in 100 subjects, and (2) functional connectivity in the context of explicit task conditions using meta‐analytic connectivity modeling (MACM) over 656 imaging experiment. Both approaches revealed a convergent functional network architecture of the aMCC with prefrontal, premotor and parietal cortices as well as anterior insula, area 44/45, cerebellum and dorsal striatum. To specifically test the role of the aMCC's task‐based functional connectivity in cognitive motor control, separate MACM analyses were conducted over “cognitive” and “action” related experimental paradigms. Both analyses confirmed the same task‐based connectivity pattern of the aMCC. While the “cognition” domain showed higher convergence of activity in supramodal association areas in prefrontal cortex and anterior insula, “action” related experiments yielded higher convergence in somatosensory and premotor areas. Secondly, to probe the functional specificity of the aMCC's convergent functional connectivity, it was compared with a neural network of intentional movement initiation. This exemplary comparison confirmed the involvement of the state independent FC network of the aMCC in the intentional generation of movements. In summary, the different experiments of the present study suggest that the aMCC constitute a key region in the network realizing intentional motor control. Hum Brain Mapp 35:2741–2753, 2014. © 2013 Wiley Periodicals, Inc .     

Dynamic brain network configurations during rest and an attention task with frequent occurrence of mind wandering

Mind wandering (MW) has become a prominent topic of neuroscientific investigation due to the importance of understanding attentional processes in our day‐to‐day experiences. Emerging evidence suggests a critical role for three large‐scale brain networks in MW: the default network (DN), the central executive network (CEN), and the salience network (SN). Advances in analytical methods for neuroimaging data (i.e., dynamic functional connectivity, DFC) demonstrate that the interactions between these networks are not static but dynamically fluctuate over time (Chang & Glover, 2010, NeuroImage, 50(1), 81–98). While the bulk of the evidence comes from studies involving resting‐state functional MRI, a few studies have investigated DFC during a task. Direct comparison of DFC during rest and task with frequent MW is scarce. The present study applies the DFC method to neuroimaging data collected from 30 participants who completed a resting‐state run followed by two runs of sustained attention to response task (SART) with embedded probes indicating a high prevalence of MW. The analysis identified five DFC states. Differences between rest and task were noted in the frequency of three DFC states. One DFC state characterized by negative DN–CEN/SN connectivity along with positive CEN–SN connectivity was more frequently observed during task vs. rest. Two DFC states, one of which was characterized by weaker connectivity between networks, were more frequently observed during rest than task. These findings suggest that the dynamic relationships between brain networks may vary as a function of whether ongoing cognitive activity unfolds in an “unconstrained” manner during rest or is “constrained” by task demands.     

Resting state and task‐induced deactivation: A methodological comparison in patients with schizophrenia and healthy controls

Changes in the default mode network (DMN) have been linked to multiple neurological disorders including schizophrenia. The anticorrelated relationship the DMN shares with task‐related networks permits the quantification of this network both during task (task‐induced deactivations: TID) and during periods of passive mental activity (extended rest). However, the effects of different methodologies (TID vs. extended rest) for quantifying the DMN in the same clinical population are currently not well understood. Moreover, several different analytic techniques, including independent component analyses (ICA) and seed‐based correlation analyses, exist for examining functional connectivity during extended resting states. The current study compared both methodologies and analytic techniques in a group of patients with schizophrenia (SP) and matched healthy controls. Results indicated that TID analyses, ICA, and seed‐based correlation all consistently identified the midline (anterior and posterior cingulate gyrus) and lateral parietal cortex as core regions of the DMN, as well as more variable involvement of temporal lobe structures. In addition, SP exhibited increased deactivation during task, as well as decreased functional connectivity with frontal regions and increased connectivity with posterior and subcortical areas during periods of extended rest. The increased posterior and reduced anterior connectivity may partially explain some of the cognitive dysfunction and clinical symptoms that are frequently associated with schizophrenia. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.     

The basal ganglia: a neural network with more than motor function

The basal ganglia is a group of subcortical nuclei involved in motor control, cognition, and emotion. Basal ganglia disorders are manifested by abnormal movement and a number of neuropsychiatric disorders. Basal ganglia nuclei are organized into sensorimotor, associative, and limbic territories based on their connectivity and function. The caudate nucleus, putamen, and subthalamic nucleus comprise the input nuclei of the basal ganglia. The internal segment of globus pallidus and substantia nigra reticulata are the output nuclei. The input and output nuclei are interconnected by direct and indirect pathways. The cerebral cortex, basal ganglia, and thalamus communicate with each other via closed (segregated) parallel as well as open (split) loops. Recent anatomic, functional, and clinical data have necessitated modifications in the classical models of local connectivity between input and output nuclei of the basal ganglia as well as in the corticobasal ganglia-thalamus-cortical loops.     

Direct synaptic connections of axons from superior colliculus with identified thalamo-amygdaloid projection neurons in the rat: Possible substrates of a subcortical visual pathway to the amygdala

The aim of the present study was to identify synaptic contacts from axons originating in the superior colliculus with thalamic neurons projecting to the lateral nucleus of the amygdala. Axons from the superior colliculus were traced with the anterograde tracers Phaseolus vulgaris leucoagglutinin or the biotinylated and fluorescent dextran amine “Miniruby.” Thalamo-amygdaloid projection neurons were identified with the retrograde tracer Fluoro-Gold. Injections of Fluoro-Gold into the lateral nucleus of the amygdala labeled neurons in nuclei of the posterior thalamus which surround the medial geniculate body, viz. the suprageniculate nucleus, the medial division of the medial geniculate body, the posterior intralaminar nucleus, and the peripeduncular nucleus. Anterogradely labeled axons from the superior colliculus terminated in the same regions of the thalamus. Tecto-thalamic axons originating from superficial collicular layers were found predominantly in the suprageniculate nucleus, whereas axons from deep collicular layers were detected in equal density in all thalamic nuclei surrounding the medial geniculate body. Double-labeling experiments revealed an overlap of projection areas in the above-mentioned thalamic nuclei. Electron microscopy of areas of overlap confirmed synaptic contacts of anterogradely labeled presynaptic profiles originating in the superficial layers of the superior colliculus with retrogradely labeled postsynaptic profiles of thalamo-amygdaloid projection neurons. These connections may represent a subcortical pathway for visual information transfer to the amygdala. J. Comp. Neurol. 403:158–170, 1999. © 1999 Wiley-Liss, Inc.     

Lesion of the centromedian thalamic nucleus in MPTP‐treated monkeys

The caudal intralaminar nuclei are a major source of glutamatergic afferents to the basal ganglia. Experiments in the 6‐hydroxydopamine rat model have shown that the parafascicular nucleus is overactive and its lesion alleviates basal ganglia neurochemical abnormalities associated with dopamine depletion. Accordingly, removal of this excitatory innervation of the basal ganglia could have a beneficial value in the parkinsonian state. To test this hypothesis, unilateral kainate‐induced chemical ablation of the centromedian thalamic nucleus (CM) has been performed in MPTP‐treated monkeys. Successful lesions restricted to the CM boundaries (n = 2) without spreading over other neighboring thalamic nuclei showed an initial, short‐lasting, and mild change in the parkinsonian motor scale but no effect against levodopa‐induced dyskinesias. The lack of significant and persistent motor improvement leads us to conclude that unilateral selective lesion of the CM alone cannot be considered as a suitable surgical approach for the treatment of PD or levodopa‐induced dyskinesias. The role of the caudal intralaminar nuclei in the pathophysiology of movement disorders of basal ganglia origin remains to be clarified. © 2007 Movement Disorder Society     

The relationship between putamen-SMA functional connectivity and sensorimotor abnormality in ESRD patients

The basal ganglia (BG) are composed of several nuclei involved in neural processing associated with integration of sensory and motor information. Recent neuroimaging studies implicated its key role in control of voluntary motor function. As the sensorimotor abnormality is common among the end-stage renal disease (ESRD) population, in the current study, we aimed to investigate the abnormal structure and functional connectivity patterns of BG in ESRD patients. Twenty-nine ESRD and twenty-nine age and gender-matched healthy controls (HC) were enrolled to compare the volume of the subsets in the BG (e.g., caudate nucleus, putamen and globus pallidus) by using the VBM analysis; resting-state functional connectivity was analyzed by a seed-based method. Compared with the HC group, ESRD patients had a smaller volume in the right putamen. Taking the right putamen as a seed region, we further found reduced functional connectivity in patients mainly between the putamen and supplementary motor area (SMA), insula, posterior mid-cingulate gyrus, and primary motor cortex. In ESRD group, the severity score of restless legs syndrome was negatively correlated with putamen-SMA functional connectivity, while the hemoglobin level was positively correlated with functional connectivity degree between the putamen and SMA. Our results revealed an abnormal volume of the putamen and its decreased functional connectivity patterns during resting state in ESRD with sensorimotor abnormalities. These preliminary results indicated that the decreased functional connectivity in putamen-SMA was associated with sensorimotor abnormalities, and anemia was correlated with this abnormal functional pattern in ESRD patients.     

Transition from spindles to generalized spike and wave discharges in the cat: Simultaneous single-cell recordings in cortex and thalamus

The relationships between the activity of the cortex and that of a “specific” (n. lateralis posterior, LP) and an intralaminar thalamic nucleus (n. centralis medialis, NCM) were studied in the cat during the transition from spontaneous spindles to generalized spike and wave (SW) discharge following i.m. penicillin injection. The EEG and extracellular single-unit activity were recorded in cortex and thalamus during the spindle stage and at different intervals after penicillin until well developed SW discharges were present. Computer-generated EEG averages and histograms of single-unit activity were triggered by either peaks of cortical or thalamic EEG transients or by cortical or thalamic action potentials. In agreement with previous observations, cortical neurons increasingly fired during the spindle wave as it was transformed into the “spike” of the SW complex, while a period of neuronal silence gradually developed as the “wave” of the SW complex emerged. Similar changes developed in the thalamus, particularly in LP, either concurrently with or more often after the onset of the changes in the cortex. Most neurons in NCM, continued to fire randomly even after well developed SWs and rhythmic neuronal discharges had developed in cortex and LP. Only $\text{4}\text{11}$ NCM neurons did ultimately exhibit a rhythmic firing pattern similar to that seen in the cortex and LP. The correlation between cortical and thalamic unit activity was low during spindles, but gradually increased during the development of SW discharges. These data confirm that the cortex is the leading element in the transition from spindles to SWs. Increasingly, in the course of this transition, cortical and thalamic neuronal firing becomes more intimately phase-locked. This mutual interrelationship appears to be more pronounced between cortex and “specific” than intralaminar thalamic nuclei.     

The effects of methylphenidate on whole brain intrinsic functional connectivity

Methylphenidate (MPH) is an indirect dopaminergic and noradrenergic agonist that is used to treat attention deficit hyperactivity disorder and that has shown therapeutic potential in neuropsychiatric diseases such as depression, dementia, and Parkinson's disease. While effects of MPH on task‐induced brain activation have been investigated, little is known about how MPH influences the resting brain. To investigate the effects of 40 mg of oral MPH on intrinsic functional connectivity, we used resting state fMRI in 54 healthy male subjects in a double‐blind, randomized, placebo‐controlled study. Functional connectivity analysis employing ICA revealed seven resting state networks (RSN) of interest. Connectivity strength between the dorsal attention network and the thalamus was increased after MPH intake. Other RSN located in association cortex areas, such as the left and right frontoparietal networks and the executive control network, showed MPH‐induced connectivity increase to sensory‐motor and visual cortex regions and connectivity decrease to cortical and subcortical components of cortico‐striato‐thalamo‐cortical circuits (CST). RSN located in sensory‐motor cortex areas showed the opposite pattern with MPH‐induced connectivity increase to CST components and connectivity decrease to sensory‐motor and visual cortex regions. Our results provide evidence that MPH does not only alter intrinsic connectivity between brain areas involved in sustained attention, but that it also induces significant changes in the cortico‐cortical and cortico‐subcortical connectivity of many other cognitive and sensory‐motor RSN. Hum Brain Mapp 35:5379–5388, 2014. © 2014 Wiley Periodicals, Inc.     

Cholinergic innervation of the human thalamus: dual origin and differential nuclear distribution.

The cholinergic innervation of the human thalamus was studied with antibodies against the enzyme choline acetyltransferase (ChAT) and nerve growth factor receptor (NGFr). Acetylcholinesterase histochemistry was used to delineate nuclear boundaries. All thalamic nuclei displayed ChAT-positive axons and varicosities. Only the medial habenula contained ChAT-positive perikarya. Some intralaminar nuclei (central medial, central lateral, and paracentral), the reticular nucleus, midline nuclei (paraventricular and reuniens), some nuclei associated with the limbic system (anterodorsal nucleus and medially situated patches in the mediodorsal nucleus) and the lateral geniculate nucleus displayed the highest density of ChAT-positive axonal varicosities. The remaining sensory relay nuclei and the nuclei interconnected with the motor and association cortex displayed a lower level of innervation. Immunoreactivity for NGFr was observed in cholinergic neurons of the basal forebrain but not in cholinergic neurons of the upper brainstem. The contribution of basal forebrain afferents to the cholinergic innervation of the human thalamus was therefore studied with the aid of NGFr-immunoreactive axonal staining. The anterior intralaminar nuclei, the reticular nucleus, and medially situated patches in the mediodorsal nucleus displayed a substantial number of NGFr-positive varicose axons, presumably originating in the basal forebrain. Rare NGFr-positive axonal profiles were also seen in many of the other thalamic nuclei. These observations suggest that thalamic nuclei affiliated with limbic structures and with the ascending reticular activating system are likely to be under particularly intense cholinergic influence. While the vast majority of thalamic cholinergic input seems to come from the upper brainstem, the intralaminar and reticular nuclei, and especially medially situated patches within the mediodorsal nucleus also appear to receive substantial cholinergic innervation from the basal forebrain.