Cortical Influences Research Articles

Selective direct motor cortical influence during naturalistic climbing.

It remains poorly resolved when and how motor cortical output directly influences limb muscle activity through descending projections, which impedes mechanistic understanding of cortical movement control. Here we addressed this in mice performing an ethologically inspired all-limb climbing behavior. We quantified the direct influence of forelimb primary motor cortex (caudal forelimb area, CFA) on muscle activity comprehensively across the muscle activity states that occur during climbing. We found that CFA informs muscle activity pattern, mainly by selectively activating certain muscles while exerting much smaller, bidirectional effects on their antagonists. From Neuropixel recordings, we identified linear combinations (components) of motor cortical activity that covary with these effects, finding that these components differ from those that covary with muscle activity or kinematics. Collectively, our results reveal an instructive direct motor cortical influence on limb muscles that is selective within a motor behavior and reliant on a new type of neural activity subspace.

Experience-dependent regulation of dopaminergic signaling in the somatosensory cortex

Dopamine critically influences reward processing, sensory perception, and motor control. Yet, the modulation of dopaminergic signaling by sensory experiences is not fully delineated. Here, by manipulating sensory experience using bilateral single-row whisker deprivation, we demonstrated that gene transcription in the dopaminergic signaling pathway (DSP) undergoes experience-dependent plasticity in both granular and supragranular layers of the primary somatosensory (barrel) cortex (S1). Sensory experience and deprivation compete for the regulation of DSP transcription across neighboring cortical columns, and sensory deprivation-induced changes in DSP are topographically constrained. These changes in DSP extend beyond cortical map plasticity and influence neuronal information processing. Pharmacological regulation of D2 receptors, a key component of DSP, revealed that D2 receptor activation suppresses excitatory neuronal excitability, hyperpolarizes the action potential threshold, and reduces the instantaneous firing rate. These findings suggest that the dopaminergic drive originating from midbrain dopaminergic neurons, targeting the sensory cortex, is subject to experience-dependent regulation and might create a regulatory feedback loop for modulating sensory processing. Finally, using topological gene network analysis and mutual information, we identify the molecular hubs of experience-dependent plasticity of DSP. These findings provide new insights into the mechanisms by which sensory experience shapes dopaminergic signaling in the brain and might help unravel the sensory deficits observed after dopamine depletion.

Prefrontal signals precede striatal signals for biased credit assignment in motivational learning biases

Actions are biased by the outcomes they can produce: Humans are more likely to show action under reward prospect, but hold back under punishment prospect. Such motivational biases derive not only from biased response selection, but also from biased learning: humans tend to attribute rewards to their own actions, but are reluctant to attribute punishments to having held back. The neural origin of these biases is unclear. Specifically, it remains open whether motivational biases arise primarily from the architecture of subcortical regions or also reflect cortical influences, the latter being typically associated with increased behavioral flexibility and control beyond stereotyped behaviors. Simultaneous EEG-fMRI allowed us to track which regions encoded biased prediction errors in which order. Biased prediction errors occurred in cortical regions (dorsal anterior and posterior cingulate cortices) before subcortical regions (striatum). These results highlight that biased learning is not a mere feature of the basal ganglia, but arises through prefrontal cortical contributions, revealing motivational biases to be a potentially flexible, sophisticated mechanism.

Changes in Cortical Composition during Gyrification in the Developing Brain

Background and Hypothesis: Abnormal brain folding has been implicated in neurodivergent conditions such as schizophrenia and autism, yet the mechanical and biological processes responsible for this process are not well understood. One current hypothesis is that cortex growth outpaces growth of the underlying white matter to drive mechanical buckling. However, mechanical stresses, such as those resulting from buckling, can also influence cellular behavior. In this study, we hypothesized that mechanical stresses from cortical folding influence processes of biological growth within the cortex, such as dendrite arborization within the neuropil and neuronal differentiation.
 Methods: To quantify change in cell body size and neuropil over the period of cortical folding, sections of the developing ferret brain (postnatal days 20, 26, 32, and 38) were stained with FluoroNissl dye, imaged with confocal microscopy, and analyzed using Fiji software. Change in percent neuropil, cell area, cell density, and overall length were quantified at upper, middle, and lower thirds of the cortex to assess the influence of bending stresses within gyri and sulci during development.
 Results: Preliminary analysis revealed a substantial increase in neuropil over time in the upper layers of the cortex. However, gyral regions expected to experience mechanical tension and increased expansion did not exhibit the hypothesized differences in neuropil or cell size. Though there was an overall increase in neuropil volume fraction and cell body size over time, throughout all layers of the cortex, these factors only accounted for roughly 2/3 of the physical growth quantified throughout these cortical layers.
 Potential Impact: Findings indicate that neuropil and cell body expansion are insufficient to fully explain the growth observed during cortical folding. These results highlight a potential role for alternative cellular processes, such as the migration of other cell types into the cortex, to induce cortical growth and folding in gyrencephalic species.

Loss of Motor Cortical Inputs to the Red Nucleus after CNS Disorders in Nonhuman Primates.

The premotor (PM) and primary motor (M1) cortical areas broadcast voluntary motor commands through multiple neuronal pathways, including the corticorubral projection that reaches the red nucleus (RN). However, the respective contribution of M1 and PM to corticorubral projections as well as changes induced by motor disorders or injuries are not known in nonhuman primates. Here, we quantified the density and topography of axonal endings of the corticorubral pathway in RN in intact monkeys, as well as in monkeys subjected to either cervical spinal cord injury (SCI), Parkinson's disease (PD)-like symptoms or primary motor cortex injury (MCI). Twenty adult macaque monkeys of either sex were injected with the biotinylated dextran amine anterograde tracer either in PM or in M1. We developed a semiautomated algorithm to reliably detect and count axonal boutons within the magnocellular and parvocellular (pRN) subdivisions of RN. In intact monkeys, PM and M1 preferentially target the medial part of the ipsilateral pRN, reflecting its somatotopic organization. Projection of PM to the ipsilateral pRN is denser than that of M1, matching previous observations for the corticotectal, corticoreticular, and corticosubthalamic projections (Fregosi et al., 2018, 2019; Borgognon et al., 2020). In all three types of motor disorders, there was a uniform and strong decrease (near loss) of the corticorubral projections from PM and M1. The RN may contribute to functional recovery after SCI, PD, and MCI, by reducing direct cortical influence. This reduction possibly privileges direct access to the final output motor system, via emphasis on the direct corticospinal projection.SIGNIFICANCE STATEMENT We measured the corticorubral projection density arising from the PM or the M1 cortices in adult macaques. The premotor cortex sent denser corticorubral projections than the primary motor cortex, as previously observed for the corticotectal, corticoreticular, and corticosubthalamic projections. The premotor cortex may thus exert more influence than primary motor cortex onto subcortical structures. We next asked whether the corticorubral motor projections undergo lesion-dependent plasticity after either cervical spinal cord injury, Parkinson's disease-like symptoms, or primary motor cortex lesion. In all three types of pathology, there was a strong decrease of the corticorubral motor projection density, suggesting that the red nucleus may contribute to functional recovery after such motor system disorders based on a reduced direct cortical influence.

Molecular characteristics and laminar distribution of prefrontal neurons projecting to the mesolimbic system.

Prefrontal cortical influence over the mesolimbic system - including the nucleus accumbens (NAc) and the ventral tegmental area (VTA) - is implicated in various cognitive processes and behavioral malfunctions. The functional versatility of this system could be explained by an underlying anatomical complexity; however, the detailed characterization of the medial prefrontal cortical (mPFC) innervation of the NAc and VTA is still lacking. Therefore, combining classical retrograde and conditional viral tracing techniques with multiple fluorescent immunohistochemistry, we sought to deliver a precise, cell- and layer-specific anatomical description of the cortico-mesolimbic pathways in mice. We demonstrated that NAc- (mPFCNAc) and VTA-projecting mPFC (mPFCVTA) populations show different laminar distribution (layers 2/3-5a and 5b-6, respectively) and express different molecular markers. Specifically, calbindin and Ntsr1 are specific to mPFCNAc neurons, while mPFCVTA neurons express high levels of Ctip2 and FoxP2, indicating that these populations are mostly separated at the cellular level. We directly tested this with double retrograde tracing and Canine adenovirus type 2-mediated viral labeling and found that there is indeed minimal overlap between the two populations. Furthermore, whole-brain analysis revealed that the projection pattern of these populations is also different throughout the brain. Taken together, we demonstrated that the NAc and the VTA are innervated by two, mostly nonoverlapping mPFC populations with different laminar distribution and molecular profile. These results can contribute to the advancement in our understanding of mesocorticolimbic functions and its disorders in future studies.

Motor cortical influence relies on task-specific activity covariation.

During limb movement, spinal circuits facilitate the alternating activation of antagonistic flexor and extensor muscles. Yet antagonist cocontraction is often required to stabilize joints, like when loads are handled. Previous results suggest that these different muscle activation patterns are mediated by separate flexion- and extension-related motor cortical output populations, while others suggest recruitment of task-specific populations. To distinguish between hypotheses, we developed a paradigm in which mice toggle between forelimb tasks requiring antagonist alternation or cocontraction and measured activity in motor cortical layer 5b. Our results conform to neither hypothesis: consistent flexion- and extension-related activity is not observed across tasks, and no task-specific populations are observed. Instead, activity covariation among motor cortical neurons dramatically changes between tasks, thereby altering the relation between neural and muscle activity. This is also observed specifically for corticospinal neurons. Collectively, our findings indicate that motor cortex drives different muscle activation patterns via task-specific activity covariation.

Effects of dry needling on muscle spasticity of the upper limb in a survivor of traumatic brain injury: a case report

BackgroundSurvivors of moderate and severe traumatic brain injury typically present with spasticity, an upper motor neuron lesion associated with hyperexcitability of the stretch reflex due to disinhibition of cortical influences on spinal cord circuits and structural and functional changes in skeletal muscle. There is growing evidence supporting the effectiveness of dry needling in abating spasticity.Case presentationThe present case aims to quantify the effects of dry needling on upper limb spastic muscles in a survivor of severe traumatic brain injury in a 27-year-old Iranian man. The treated muscles were biceps brachii, brachialis, flexor digitorum superficialis and profundus, flexor carpi radialis, flexor carpi ulnaris, opponens pollicis, and adductor pollicis. Outcome measures were evaluated before and 1 hour after the intervention. Our results showed that the patient’s upper limb recovery stage and hand function improved one grade according to Brunnstrom recovery stages. Spasticity assessed using the Modified Modified Ashworth Scale in all movements showed one-grade abatement, except in the forearm pronator. Passive resistance force decreased in all movements except in forearm supination. Active range of motion and passive range of motion increased in all movements except in active and passive forearm supination. Hand dexterity improved in both affected and unaffected hands.ConclusionsResults shown that dry needling could be a favorable option for reducing spasticity.

The Effects of an Acute Maximal Seated Lumbar Spine Flexion Exposure on Low Back Mechanical Pain Sensitivity.

Viscoelastic creep generated in the lumbar spine following sustained spine flexion may affect the relationship between tissue damage and perceived pain. Two processes supporting this altered relationship include altered neural feedback and inflammatory processes. Our purpose was to determine how low back mechanical pain sensitivity changes following seated lumbar spine flexion using pressure algometry in a repeated-measures, cross-sectional laboratory design. Thirty-eight participants underwent a 10-minute sustained seated maximal flexion exposure with a 40-minute standing recovery period. Pressure algometry assessed pressure pain thresholds and the perceived intensity and unpleasantness of fixed pressures. Accelerometers measured spine flexion angles, and electromyography measured muscular activity during flexion. The flexion exposure produced 4.4° (2.7°) of creep that persisted throughout the entire recovery period. The perception of low back stimulus unpleasantness was elevated immediately following the exposure, 20 minutes before a delayed increase in lumbar erector spinae muscle activity. Women reported the fixed pressures to be more intense than men. Sustained flexion had immediate consequences to the quality of mechanical stimulus perceived but did not alter pressure pain thresholds. Neural feedback and inflammation seemed unlikely mechanisms for this given the time and direction of pain sensitivity changes, leaving a postulated cortical influence.

Transient increase in recurrent inhibition in amyotrophic lateral sclerosis as a putative protection from neurodegeneration.

Adaptive mechanisms in spinal circuits are likely involved in homeostatic responses to maintain motor output in amyotrophic lateral sclerosis. Given the role of Renshaw cells in regulating the motoneuron input/output gain, we investigated the modulation of heteronymous recurrent inhibition. Electrical stimulations were used to activate recurrent collaterals resulting in the Hoffmann reflex depression. Inhibitions from soleus motor axons to quadriceps motoneurons, and vice versa, were tested in 38 patients and matched group of 42 controls. Compared with controls, the mean depression of quadriceps reflex was larger in patients, while that of soleus was smaller, suggesting that heteronymous recurrent inhibition was enhanced in quadriceps but reduced in soleus. The modulation of recurrent inhibition was linked to the size of maximal direct motor response and lower limb dysfunctions, suggesting a significant relationship with the integrity of the target motoneuron pool and functional abilities. No significant link was found between the integrity of motor axons activating Renshaw cells and the level of inhibition. Enhanced inhibition was particularly observed in patients within the first year after symptom onset and with slow progression of lower limb dysfunctions. Normal or reduced inhibitions were mainly observed in patients with motor weakness first in lower limbs and greater dysfunctions in lower limbs. We provide the first evidence for enhanced recurrent inhibition and speculate that Renshaw cells might have transient protective role on motoneuron by counteracting hyperexcitability at early stages. Several mechanisms likely participate including cortical influence on Renshaw cell and reinnervation by slow motoneurons.

Blockade of vasopressin receptors reduces the threshold pressure of micturition reflex in female rats.

The mechanisms involved in urinary bladder control are not fully understood, but it is well accepted that a complex central network is involved in micturition control. The micturition reflex can be modulated by direct cortical influence through facilitatory and inhibitory mechanisms. In addition, humoral mechanisms are involved in the bladder control. Vasopressin increases bladder contraction and intravesical pressure. This study sought to investigate the effect of intravenous injections of vasopressin receptor antagonists on cystometric parameters in anesthetized female rats. Isoflurane anesthetized adult female Wistar rats underwent femoral artery and vein cannulation for arterial pressure (AP) and heart rate (HR) recordings, and infusion of drugs, respectively. The bladder was also cannulated for intravesical pressure (IP) recordings and infusion of saline (10 mL/h) for cystometric evaluation. After baseline AP, HR and IP recordings, saline (vehicle, 1 mL/kg), V1a (5 μg/kg) or V2 receptor antagonist (5 μg/kg) was injected i.v. and after 25 min the cystometry was carried out. Neither saline nor V1a or V2 receptor blockade evoked any change in AP, HR and IP. Nevertheless, during cystometry, the threshold pressure of the micturition reflex was significantly reduced in rats with V1a (to 19.30 ± 2.39 mmHg) and V2 receptor blockade (to 19.88 ± 2.49 mmHg) compared to the saline group (28.85 ± 2.06 mmHg, p = 0.014). No difference was observed in the other cystometric parameters. Therefore, the data suggest that blockade of V1a and V2 receptors reduces the threshold pressure of the micturition reflex and does not influence other cystometric parameters in anesthetized female Wistar rats.

Loss of Awareness or Urinary Dysfunction? Investigating Amyloidosis and Urinary Physiology in a Transgenic Mouse

Alzheimer’s disease (AD) is a devastating disorder primarily affecting older adults and is the most common neurodegenerative disease in the US. More than one in three AD patients experience AD-associated urinary dysfunction (ADUD), which directly contributes to their institutionalization. While ADUD has been clinically regarded as a result of poor cognitive control over urinary function, the physiology underlying loss of urinary control remains unknown. We hypothesize that amyloidosis in the CNS results in pathologic changes in urinary structure and function. Tg-APP/PS1DE9 mice were used before plaque deposition (4-6 months) and after plaque accumulation (8-10 months) and compared to WT littermates. Behavioral assays (open field testing and voiding spot assays) were performed to assess cortical function. Pressure-flow cystometry was conducted under urethane anesthesia to assess autonomic control of urinary function without cortical influence. Pharmacomyography of bladder strips was used to determine tissue-level changes in the absence of CNS input. In Tg-APP/PS1DE9 mice, plaque accumulation resulted in significant cystometric changes to voiding phase parameters, but not storage phase parameters. Pharmacologic studies showed decreased sensitivity to adrenergic stimulation without change in muscarinic sensitivity. Behavioral assays demonstrated significant differences between transgenic animals and WT in locomotion and voiding spot sizes. We interpret our data to support AD-related pathology of Aβ accumulation results in a distinct urinary phenotype in our model, analogous to the ADUD observed in AD patients. Establishing and verifying models of ADUD may improve the efficacy of treating ADUD and increase quality of life for patients and their caregivers.

Transcranial magnetic stimulation entrains alpha oscillatory activity in occipital cortex

Parieto-occipital alpha rhythms (8–12 Hz) underlie cortical excitability and influence visual performance. Whether the synchrony of intrinsic alpha rhythms in the occipital cortex can be entrained by transcranial magnetic stimulation (TMS) is an open question. We applied 4-pulse, 10-Hz rhythmic TMS to entrain intrinsic alpha oscillators targeting right V1/V2, and tested four predictions with concurrent electroencephalogram (EEG): (1) progressive enhancement of entrainment across time windows, (2) output frequency specificity, (3) dependence on the intrinsic oscillation phase, and (4) input frequency specificity to individual alpha frequency (IAF) in the neural signatures. Two control conditions with an equal number of pulses and duration were arrhythmic-active and rhythmic-sham stimulation. The results confirmed the first three predictions. Rhythmic TMS bursts significantly entrained local neural activity. Near the stimulation site, evoked oscillation amplitude and inter-trial phase coherence (ITPC) were increased for 2 and 3 cycles, respectively, after the last TMS pulse. Critically, ITPC following entrainment positively correlated with IAF rather than with the degree of similarity between IAF and the input frequency (10 Hz). Thus, we entrained alpha-band activity in occipital cortex for ~ 3 cycles (~ 300 ms), and IAF predicts the strength of entrained occipital alpha phase synchrony indexed by ITPC.

Linking Penetrance and Transcription in DYT-THAP1: Insights From a Human iPSC-Derived Cortical Model.

The THAP1 gene encodes a transcription factor, and pathogenic variants cause a form of autosomal dominant, isolated dystonia (DYT-THAP1) with reduced penetrance. Factors underlying both reduced penetrance and the disease mechanism of DYT-THAP1 are largely unknown. We performed transcriptome analysis on 29 cortical neuronal precursors derived from human-induced pluripotent stem cell lines generated from manifesting and nonmanifesting THAP1 mutation carriers and control individuals. Whole transcriptome analysis showed a penetrance-linked signature with expressional changes more pronounced in the group of manifesting (MMCs) than in nonmanifesting mutation carriers (NMCs) when compared to controls. A direct comparison of the transcriptomes in MMCs versus NMCs showed significant upregulation of the DRD4 gene in MMCs. A gene set enrichment analysis demonstrated alterations in various neurotransmitter release cycle pathways, extracellular matrix organization, and deoxyribonucleic acid methylation between MMCs and NMCs. When specifically considering transcription factors, the expression of YY1 and SIX2 differed in MMCs versus NMCs. Further, THAP1 was upregulated in the group of MMCs. To our knowledge, this is the first report systematically analyzing reduced penetrance in DYT-THAP1 in a human model using transcriptomes. Our findings indicate that transcriptional alterations during cortical development influence DYT-THAP1 pathogenesis and penetrance. We reinforce previously linked pathways including dopamine and eukaryotic translation initiation factor 2 alpha signaling in the pathogenesis of dystonia including DYT-THAP1 and suggest extracellular matrix organization and deoxyribonucleic acid methylation as mediators of disease protection. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Top-down coordination of local cortical state during selective attention

SummarySpontaneous fluctuations in cortical excitability influence sensory processing and behavior. These fluctuations, long thought to reflect global changes in cortical state, were recently found to be modulated locally within a retinotopic map during spatially selective attention. We report that periods of vigorous (On) and faint (Off) spiking activity, the signature of cortical state fluctuations, are coordinated across brain areas with retinotopic precision. Top-down attention enhanced interareal local state coordination, traversing along the reverse cortical hierarchy. The extent of local state coordination between areas was predictive of behavioral performance. Our results show that cortical state dynamics are shared across brain regions, modulated by cognitive demands and relevant for behavior.

The mind-body problem: Circuits that link the cerebral cortex to the adrenal medulla

Which regions of the cerebral cortex are the origin of descending commands that influence internal organs? We used transneuronal transport of rabies virus in monkeys and rats to identify regions of cerebral cortex that have multisynaptic connections with a major sympathetic effector, the adrenal medulla. In rats, we also examined multisynaptic connections with the kidney. In monkeys, the cortical influence over the adrenal medulla originates from 3 distinct networks that are involved in movement, cognition, and affect. Each of these networks has a human equivalent. The largest influence originates from a motor network that includes all 7 motor areas in the frontal lobe. These motor areas are involved in all aspects of skeletomotor control, from response selection to motor preparation and movement execution. The motor areas provide a link between body movement and the modulation of stress. The cognitive and affective networks are located in regions of cingulate cortex. They provide a link between how we think and feel and the function of the adrenal medulla. Together, the 3 networks can mediate the effects of stress and depression on organ function and provide a concrete neural substrate for some psychosomatic illnesses. In rats, cortical influences over the adrenal medulla and the kidney originate mainly from 2 motor areas and adjacent somatosensory cortex. The cognitive and affective networks, present in monkeys, are largely absent in rats. Thus, nonhuman primate research is essential to understand the neural substrate that links cognition and affect to the function of internal organs.

Disynaptic cerebrocerebellar pathways originating from multiple functionally distinct cortical areas

The cerebral cortex and cerebellum both play important roles in sensorimotor processing, however, precise connections between these major brain structures remain elusive. Using anterograde mono-trans-synaptic tracing, we elucidate cerebrocerebellar pathways originating from primary motor, sensory, and association cortex. We confirm a highly organized topography of corticopontine projections in mice; however, we found no corticopontine projections originating from primary auditory cortex and detail several potential extra-pontine cerebrocerebellar pathways. The cerebellar hemispheres were the major target of resulting disynaptic mossy fiber terminals, but we also found at least sparse cerebrocerebellar projections to every lobule of the cerebellum. Notably, projections originating from association cortex resulted in less laterality than primary sensory/motor cortices. Within molecularly defined cerebellar modules we found spatial overlap of mossy fiber terminals, originating from functionally distinct cortical areas, within crus I, paraflocculus, and vermal regions IV/V and VI - highlighting these regions as potential hubs for multimodal cortical influence.

Synchronisation of Neural Oscillations and Cross-modal Influences.

At any given moment, we receive multiple signals from our different senses. Prior research has shown that signals in one sensory modality can influence neural activity and behavioural performance associated with another sensory modality. Recent human and nonhuman primate studies suggest that such cross-modal influences in sensory cortices are mediated by the synchronisation of ongoing neural oscillations. In this review, we consider two mechanisms proposed to facilitate cross-modal influences on sensory processing, namely cross-modal phase resetting and neural entrainment. We consider how top-down processes may further influence cross-modal processing in a flexible manner, and we highlight fruitful directions for further research.

Эффекты стимуляции инфралимбической коры на реакции нейронов каудальной вентролатеральной ретикулярной формации, вызванные ноцицептивным раздражением толстой кишки крысы

The infralimbic cortex of the cerebral hemispheres is characterized by an extensive system of afferent and efferent connections with cortical, subcortical, bainstem structures and the spinal cord, which ensure its participation in the higher mechanisms of regulation of the functions of the visceral sphere. At the same time, the involvement of the infralimbic cortex in the mechanisms of cortical modulation of visceral nociception, both acute and chronic, seems to be poorly understood. In this work, using an experimental model of abdominal pain on two groups of urethane anesthetized rats (normal rats and rats with experimental colitis), we studied the effects of electrical stimulation of the infralimbic cortex on the neuronal (responses of neurons of the caudal ventrolateral reticular formation) and systemic (changes in arterial blood pressure) reactions induced by nociceptive distension of the colorectal region of colon. It has been found that in rats of both groups nociceptive colorectal distension was accompanied by both excitatory and inhibitory reactions of neurons of the ventrolateral reticular formation, as well as depressor changes in blood pressure. Electrical stimulation of the infralimbic cortex increased excitatory and decreased inhibitory neuronal responses to visceral painful stimulation and also enhanced nociceptive depressor responses in both normal rats and rats with colitis. This effect was more pronounced in the group of healthy animals. In general, the influence of the infralimbic cortex on nociceptive neurons of the ventrolateral reticular formation and vascular responses to visceral pain can be considered as facilitating visceral nociception. Quantitative differences in the effects of cortical stimulation in normal rats and rats with colitis are possibly related to differences in the brain processing of acute visceral pain and pain complicated by chronic inflammation. One of the possible mechanisms of cortical influence on visceral nociception may be modulation of the current activity of nociceptive neurons of the caudal ventrolateral reticular formation, directly or indirectly involved in the descending control of visceral pain.

The mind–body problem: Circuits that link the cerebral cortex to the adrenal medulla

Which regions of the cerebral cortex are the origin of descending commands that influence internal organs? We used transneuronal transport of rabies virus in monkeys and rats to identify regions of cerebral cortex that have multisynaptic connections with a major sympathetic effector, the adrenal medulla. In rats, we also examined multisynaptic connections with the kidney. In monkeys, the cortical influence over the adrenal medulla originates from 3 distinct networks that are involved in movement, cognition, and affect. Each of these networks has a human equivalent. The largest influence originates from a motor network that includes all 7 motor areas in the frontal lobe. These motor areas are involved in all aspects of skeletomotor control, from response selection to motor preparation and movement execution. The motor areas provide a link between body movement and the modulation of stress. The cognitive and affective networks are located in regions of cingulate cortex. They provide a link between how we think and feel and the function of the adrenal medulla. Together, the 3 networks can mediate the effects of stress and depression on organ function and provide a concrete neural substrate for some psychosomatic illnesses. In rats, cortical influences over the adrenal medulla and the kidney originate mainly from 2 motor areas and adjacent somatosensory cortex. The cognitive and affective networks, present in monkeys, are largely absent in rats. Thus, nonhuman primate research is essential to understand the neural substrate that links cognition and affect to the function of internal organs.