David J. Levinthal

The Spinothalamic System Targets Motor and Sensory Areas in the Cerebral Cortex of Monkeys

Classically, the spinothalamic (ST) system has been viewed as the major pathway for transmitting nociceptive and thermoceptive information to the cerebral cortex. There is a long-standing controversy about the cortical targets of this system. We used anterograde transneuronal transport of the H129 strain of herpes simplex virus type 1 in the Cebus monkey to label the cortical areas that receive ST input. We found that the ST system reaches multiple cortical areas located in the contralateral hemisphere. The major targets are granular insular cortex, secondary somatosensory cortex and several cortical areas in the cingulate sulcus. It is noteworthy that comparable cortical regions in humans consistently display activation when subjects are acutely exposed to painful stimuli. We next combined anterograde transneuronal transport of virus with injections of a conventional tracer into the ventral premotor area (PMv). We used the PMv injection to identify the cingulate motor areas on the medial wall of the hemisphere. This combined approach demonstrated that each of the cingulate motor areas receives ST input. Our meta-analysis of imaging studies indicates that the human equivalents of the three cingulate motor areas also correspond to sites of pain-related activation. The cingulate motor areas in the monkey project directly to the primary motor cortex and to the spinal cord. Thus, the substrate exists for the ST system to have an important influence on the cortical control of movement.

Motor, cognitive, and affective areas of the cerebral cortex influence the adrenal medulla

Significance How does the “mind” (brain) influence the “body” (internal organs)? We identified key areas in the primate cerebral cortex that are linked through multisynaptic connections to the adrenal medulla. The most substantial influence originates from a broad network of motor areas that are involved in all aspects of skeletomotor control from response selection to motor preparation and movement execution. A smaller influence originates from a network in medial prefrontal cortex that is involved in the regulation of cognition and emotion. Thus, cortical areas involved in the control of movement, cognition, and affect are potential sources of central commands to influence sympathetic arousal. These results provide an anatomical basis for psychosomatic illness where mental states can alter organ function. Modern medicine has generally viewed the concept of “psychosomatic” disease with suspicion. This view arose partly because no neural networks were known for the mind, conceptually associated with the cerebral cortex, to influence autonomic and endocrine systems that control internal organs. Here, we used transneuronal transport of rabies virus to identify the areas of the primate cerebral cortex that communicate through multisynaptic connections with a major sympathetic effector, the adrenal medulla. We demonstrate that two broad networks in the cerebral cortex have access to the adrenal medulla. The larger network includes all of the cortical motor areas in the frontal lobe and portions of somatosensory cortex. A major component of this network originates from the supplementary motor area and the cingulate motor areas on the medial wall of the hemisphere. These cortical areas are involved in all aspects of skeletomotor control from response selection to motor preparation and movement execution. The second, smaller network originates in regions of medial prefrontal cortex, including a major contribution from pregenual and subgenual regions of anterior cingulate cortex. These cortical areas are involved in higher-order aspects of cognition and affect. These results indicate that specific multisynaptic circuits exist to link movement, cognition, and affect to the function of the adrenal medulla. This circuitry may mediate the effects of internal states like chronic stress and depression on organ function and, thus, provide a concrete neural substrate for some psychosomatic illness.

The Motor Cortex Communicates with the Kidney

We used retrograde transneuronal transport of rabies virus from the rat kidney to identify the areas of the cerebral cortex that are potential sources of central commands for the neural regulation of this organ. Our results indicate that multiple motor and nonmotor areas of the cerebral cortex contain output neurons that indirectly influence kidney function. These cortical areas include the primary motor cortex (M1), the rostromedial motor area (M2), the primary somatosensory cortex, the insula and other regions surrounding the rhinal fissure, and the medial prefrontal cortex. The vast majority of the output neurons from the cerebral cortex were located in two cortical areas, M1 (68%) and M2 (15%). If the visceromotor functions of M1 and M2 reflect their skeletomotor functions, then the output to the kidney from each cortical area could make a unique contribution to autonomic control. The output from M1 could add precision and organ-specific regulation to descending visceromotor commands, whereas the output from M2 could add anticipatory processing which is essential for allostatic regulation. We also found that the output from M1 and M2 to the kidney originates predominantly from the trunk representations of these two cortical areas. Thus, a map of visceromotor representation appears to be embedded within the classic somatotopic map of skeletomotor representation.

Adding to the Burden: Gastrointestinal Symptoms and Syndromes in Multiple Sclerosis

Background. Multiple sclerosis (MS) patients often suffer from gastrointestinal (GI) symptoms. However, the full extent and prevalence of such symptoms are not clearly established. Thus, we sought to define the prevalence of GI symptoms and syndromes in those with MS. Methods. 218 MS patients completed self-reported demographic and clinical data questionnaires as well as several standardized surveys probing MS severity and GI health. Results. Nearly two thirds (65.6%) of patients endorsed at least one persistent GI symptom. Constipation (36.6%), dysphagia (21.1%), and fecal incontinence (15.1%) were common. Surprisingly, nearly 30% (28.4%) of the patients reported dyspeptic symptoms. Using validated diagnostic algorithms, patients met criteria for functional dysphagia (14.7%), functional dyspepsia (16.5%), functional constipation (31.7%), and IBS (19.3%), among others. Functional dysphagia, functional dyspepsia, and IBS were significantly more common in those with self-identified mood disorders. Conclusions. Constipation, fecal incontinence, and dysphagia are indeed frequent symptoms seen in MS patients. We also noted a ~30% prevalence of dyspepsia in this population. The mechanisms driving this association are not clear and require further study. However, due to this high prevalence, dyspeptic symptoms should be incorporated into the routine assessment of MS patients and, if found, may warrant collaborative referral with a GI specialist.

Anorectal Dysfunction in Multiple Sclerosis: A Systematic Review

Constipation and fecal incontinence are common in patients with neuromuscular diseases. Despite their high prevalence and potential impact on overall quality of life, few studies have addressed anorectal dysfunction in patients with multiple sclerosis (MS). The goal of this paper is to define the prevalence, pathophysiology, impact, and potential treatment of constipation and incontinence in MS patients. Methods. The PubMed database was searched for English language publications between January 1973 and December 2011. Articles were reviewed to assess the definition of the study population, duration, type and severity of MS, sex distribution, prevalence, impact, results of physiologic testing, and treatments. Results. The reported prevalence of constipation and fecal incontinence ranged around 40%. Anorectal dysfunction significantly affected patients with nearly 1 in 6 patients limiting social activities or even quitting work due to symptoms. Caregivers listed toileting as a common and significant burden. The only randomized controlled trial showed a marginal improvement of constipation with abdominal massage. All other reports lacked control interventions and only demonstrated improvement in individuals with milder symptoms. Conclusion. Anorectal dysfunction is a common manifestation in MS that significantly affects quality of life. Therapies are at best moderately effective and often cumbersome, highlighting the need for simple and more helpful interventions.

Adult cyclical vomiting syndrome: a disorder of allostatic regulation?

Cyclic vomiting syndrome (CVS) is an idiopathic illness characterized by stereotypic and sudden-onset episodes of intense retching and repetitive vomiting that are often accompanied by severe abdominal pain. Many associated factors that predict CVS attacks, such as prolonged periods of fasting, sleep deprivation, physical and emotional stress, or acute anxiety, implicate sympathetic nervous system activation as a mechanism that may contribute to CVS pathogenesis. Furthermore, adult patients with CVS tend to have a history of early adverse life events, mood disorders, chronic stress, and drug abuse—all associations that may potentiate sympathetic neural activity. In this review, we set forth a conceptual model in which CVS is viewed as a brain disorder involving maladaptive plasticity within central neural circuits important for allostatic regulation of the sympathetic nervous system. This model not only can account for the varied clinical observations that are linked with CVS, but also has implications for potential therapeutic interventions. Thus, it is likely that cognitive behavioral therapy, stress management (“mind–body”) interventions, regular exercise, improved sleep, and avoidance of cannabis and opiate use could have positive influences on the clinical course for patients with CVS.

The Cyclic Vomiting Syndrome Threshold: A Framework for Understanding Pathogenesis and Predicting Successful Treatments

Cyclic vomiting syndrome (CVS) is an uncommon, idiopathic disorder defined by recurrent, sudden-onset attacks of repetitive retching and vomiting that are separated by symptom-free intervals. CVS was long regarded as a disorder primarily experienced by children but is now known to present de novo in adulthood. Adult CVS has garnered more research attention over the past 20 years, and these efforts have identified some acute and prophylactic treatments for this disorder. However, CVS still lacks a unifying disease model, and this has hindered the development of new therapies. Here adult CVS is reframed as a neurogenic disorder, driven by various endophenotypic factors that shape patterns of activity within the neural circuits required for disease expression. The concept of the “CVS threshold” is put forth in parallel with exploring the remarkable similarity of adult CVS with features of chronic migraine, epilepsy, and panic disorder. Because of such shared neural mechanisms and overlapping endophenotypes, many therapies that have been developed for these other disorders could also be useful in managing CVS. This review seeks to achieve three primary aims: (1) to develop a comprehensive, explanatory framework for adult CVS pathogenesis, (2) to use this framework for identifying potentially novel therapies for CVS, and (3) to describe future research directions that are needed to move the field forward.

Effective Constipation Treatment Changes More Than Bowel Frequency: A Systematic Review and Meta-Analysis

Background/Aims The marketing of newer agents for treatment of constipation and irritable bowel syndrome with constipation (IBS-C) emphasize improvements in abdominal pain. However, it is not clear whether this observation reflects a unique visceral analgesic effect of these agents or is a general feature of effective laxation. We sought to determine the relationship between improvements in bowel frequency and decreases in abdominal pain in clinical trials of patients with constipation or IBS-C. Methods We searched “PubMed” and “Embase” databanks for clinical trials in patients with constipation or IBS-C, targeting publications that provided detailed data on bowel movement frequency and pain intensity before and after an intervention. We abstracted the results and performed meta-analytic and meta-regression analyses. Results Twenty-seven trials (16 constipation and 11 IBS) met entry criteria. Baseline weekly bowel movement frequency was low with 2.35 (2.07–2.64) with differences between constipation (2.00 [1.62–2.38]) and IBS-C (2.77 [2.40–3.14]; Q = 8.18; P = 0.002). Studies reported moderate pain levels (2.12 [1.81–2.42]) with comparable baseline levels in constipation (2.02 [1.63–2.42]) and IBS-C (2.35 [2.10–2.60]; Q = 1.92; P = 0.167). Treatments increased bowel frequency by 2.17 [1.88–2.47] and lowered pain ratings by 0.58 [0.49–0.68]. Meta-regression demonstrated a significant correlation between treatment-induced increases in bowel frequency and decreased pain ratings. Conclusions Our analysis suggests that reduction of abdominal pain observed in clinical trials of constipation and IBS-C is associated with laxation, and may not require specific drug mechanisms, thus arguing against a unique advantage of newer agents over traditional laxatives in the treatment of constipation and IBS-C.

Hospitalization rates and discharge status in multiple sclerosis.

Management of multiple sclerosis (MS) has shifted from supportive to disease modifying therapy. Considering the increasingly widespread adoption of this approach in managing MS patients, we hypothesized that hospitalizations and surrogates of disease-related complications should have declined during the last decade. Methods. Using the Nationwide Inpatient Sample, hospitalizations for MS and associated secondary diagnoses and procedures as well as discharge status were examined. Time trends were examined for different age cohorts focusing on the period from 2001 to 2010. Results. During the preceding decade, annual hospitalizations for MS increased by 40%, with stable rates in all age groups except geriatric patients, who accounted for a significantly higher fraction of admissions. Nursing home transfers as a surrogate marker of disability remained unchanged for all age groups. Similarly, urinary tract infections, the need for skin debridement, or gastrostomy tube placement did not vary during the decade. Conclusion. During a time of increased adoption of disease modifying therapy, MS-related hospitalizations continued to increase and surrogate measures of disability in admitted patients remained stable, demonstrating the still significant impact of the disease on affected individuals.

Pieces of a puzzle: Permeability, proinflammatory pathways and pain?

Chronic pain is very common and often not explained by clearly demonstrable structural and/or biochemical abnormalities. Irritable bowel syndrome (IBS) is a very important example of this large group of medically unexplained disorders that manifest with pain and/or discomfort. IBS alone accounts for millions of consultative visits and billions in direct and indirect healthcare costs each year. Many potential mechanisms have been proposed to explain the development of IBS. Within the last 100 years, we seemingly have gone full circle. Although initially described as ‘mucous colitis’ (e.g., [15]), detailed studies could not confirm the presence of inflammation, which led clinicians and researchers to focus on other possible explanations ranging from dysmotility to hypersensitivity. More recently, the attention returned to inflammation with subtle changes rather than prominent and obvious findings being described in IBS. The article by Zhou et al. in the current issue of Pain provides yet another piece in this puzzle, showing that increased intestinal permeability, likely a consequence of mild inflammation, is associated with increased pain ratings in IBS patients [16].