Michael Noll-Hussong

Calbindin in Cerebellar Purkinje Cells Is a Critical Determinant of the Precision of Motor Coordination

Long-term depression (LTD) of Purkinje cell–parallel fiber synaptic transmission is a critical determinant of normal cerebellar function. Impairment of LTD through, for example, disruption of the metabotropic glutamate receptor–IP3–calcium signaling cascade in mutant mice results in severe deficits of both synaptic transmission and cerebellar motor control. Here, we demonstrate that selective genetic deletion of the calcium-binding protein calbindin D-28k (calbindin) from cerebellar Purkinje cells results in distinctly different cellular and behavioral alterations. These mutants display marked permanent deficits of motor coordination and sensory processing. This occurs in the absence of alterations in a form of LTD implicated in the control of behavior. Analysis of synaptically evoked calcium transients in spines and dendrites of Purkinje cells demonstrated an alteration of time course and amplitude of fast calcium transients after parallel or climbing fiber stimulation. By contrast, the delayed metabotropic glutamate receptor-mediated calcium transients were normal. Our results reveal a unique role of Purkinje cell calbindin in a specific form of motor control and suggest that rapid calcium buffering may directly control behaviorally relevant neuronal signal integration.

Frequency shifts in the anterior default mode network and the salience network in chronic pain disorder

BackgroundRecent functional imaging studies on chronic pain of various organic etiologies have shown significant alterations in both the spatial and the temporal dimensions of the functional connectivity of the human brain in its resting state. However, it remains unclear whether similar changes in intrinsic connectivity networks (ICNs) also occur in patients with chronic pain disorder, defined as persistent, medically unexplained pain.MethodsWe compared 21 patients who suffered from chronic pain disorder with 19 age- and gender-matched controls using 3T-fMRI. All neuroimaging data were analyzed using both independent component analysis (ICA) and power spectra analysis.ResultsIn patients suffering from chronic pain disorder, the fronto-insular ‘salience’ network (FIN) and the anterior default mode network (aDMN) predominantly oscillated at higher frequencies (0.20 - 0.24 Hz), whereas no significant differences were observed in the posterior DMN (pDMN) and the sensorimotor network (SMN).ConclusionsOur results indicate that chronic pain disorder may be a self-sustaining and endogenous mental process that affects temporal organization in terms of a frequency shift in the rhythmical dynamics of cortical networks associated with emotional homeostasis and introspection.

Functional relaxation as complementary therapy in irritable bowel syndrome: a randomized, controlled clinical trial.

OBJECTIVES Irritable bowel syndrome (IBS) is a frequently disabling and almost invariably distressing disease with a high overall prevalence. Numerous trials identified the importance of psychogenic and emotional etiological factors, and this is obvious in clinical practice. Although relaxation techniques are frequently recommended, there is still a lack of evidence for their efficacy in the management of IBS. This study therefore aims to determine the efficacy of functional relaxation (FR) in IBS. SUBJECTS The subjects were 80 patients with IBS. INTERVENTIONS Participants were randomly allocated either to FR or to enhanced medical care (EMC: treatment as usual plus two counseling interviews) as control intervention with 2 weekly sessions over the 5-week trial each. Thirty-nine (39) patients completed FR and 39 received EMC. OUTCOME MEASURES An impairment-severity score (IS) was employed as the primary outcome parameter with assessment at baseline, after treatment, and again after 3-month follow-up. RESULTS FR was significantly superior to EMC with a standardized effect size of 0.85. The achieved effects through FR remained stable in terms of psychic and bodily impairment after 3-month follow-up. CONCLUSIONS The results of our trial suggest a positive effect of FR training on subjective functional impairment in the IS, if provided in addition to treatment as usual (TAU). There appears to be a clinically relevant long-term benefit of FR as a nonpharmacological and complementary therapy approach in IBS.

Functional Relaxation and Guided Imagery as Complementary Therapy in Asthma: A Randomized Controlled Clinical Trial

Background: Asthma is a frequently disabling and almost invariably distressing disease that has a high overall prevalence. Although relaxation techniques and hypnotherapeutic interventions have proven their effectiveness in numerous trials, relaxation therapies are still not recommended in treatment guidelines due to a lack of methodological quality in many of the trials. Therefore, this study aims to investigate the efficacy of the brief relaxation technique of functional relaxation (FR) and guided imagery (GI) in adult asthmatics in a randomized controlled trial. Methods: 64 patients with extrinsic bronchial asthma were treated over a 4-week period and assessed at baseline, after treatment and after 4 months, for follow-up. 16 patients completed FR, 14 GI, 15 both FR and GI (FR/GI) and 13 received a placebo relaxation technique as the control intervention (CI). The forced expiratory volume in the first second (FEV1) as well as the specific airway resistance (sRaw) were employed as primary outcome measures. Results: Participation in FR, GI and FR/GI led to increases in FEV1 (% predicted) of 7.6 ± 13.2, 3.3 ± 9.8, and 8.3 ± 21.0, respectively, as compared to –1.8 ± 11.1 in the CI group at the end of the therapy. After follow-up, the increases in FEV1 were 6.9 ± 10.3 in the FR group, 4.4 ± 7.3 in the GI and 4.5 ± 8.1 in the FR/GI, compared to –2.8 ± 9.2 in the CI. Improvements in sRaw (% predicted) were in keeping with the changes in FEV1 in all groups. Conclusions: Our study confirms a positive effect of FR on respiratory parameters and suggests a clinically relevant long-term benefit from FR as a nonpharmacological and complementary therapy treatment option.

Functional network connectivity of pain-related resting state networks in somatoform pain disorder: an exploratory fMRI study.

BACKGROUND Without stimulation, the human brain spontaneously produces highly organized, low-frequency fluctuations of neural activity in intrinsic connectivity networks (ICNs). Furthermore, without adequate explanatory nociceptive input, patients with somatoform pain disorder experience pain symptoms, thus implicating a central dysregulation of pain homeostasis. The present study aimed to test whether interactions among pain-related ICNs, such as the default mode network (DMN), cingular-insular network (CIN) and sensorimotor network (SMN), are altered in somatoform pain during resting conditions. METHODS Patients with somatoform pain disorder and healthy controls underwent resting functional magnetic resonance imaging that lasted 370 seconds. Using a data-driven approach, the ICNs were isolated, and the functional network connectivity (FNC) was computed. RESULTS Twenty-one patients and 19 controls enrolled in the study. Significant FNC (p < 0.05, corrected for false discovery rate) was detected between the CIN and SMN/anterior DMN, the anterior DMN and posterior DMN/SMN, and the posterior DMN and SMN. Interestingly, no group differences in FNC were detected. LIMITATIONS The most important limitation of this study was the relatively short resting state paradigm. CONCLUSION To our knowledge, our results demonstrated for the first time the resting FNC among pain-related ICNs. However, our results suggest that FNC signatures alone are not able to characterize the putative central dysfunction underpinning somatoform pain disorder.

Acupuncture-Induced Pain Relief and the Human Brain's Default Mode Network - an Extended View of Central Effects of Acupuncture Analgesia

As a complementary medical procedure, acupuncture has a significant impact on the treatment of acute and chronic pain. Though the physiological mechanisms behind this method are still unclear, acupuncture has been claimed to rely also on changes in the central nervous system. Recent functional imaging studies indicate that the so-called default mode network (DMN) which consists of cortical midline structures and lateral parietal regions plays an important role in these processes. This brief overview describes the effects of analgesic acupuncture on the DMN architecture. The stronger interplay between systems dedicated to endogenous analgesia (periaqueductal gray), affective processing (anterior cingulate cortex, amygdala), memory (hippocampus), and self-projective thinking (DMN) following this therapy supports the notion that acupuncture is a mind-body therapy which helps to reintegrate important neural dimensions of inner life and to establish psychophysical pain homeostasis.

Neural correlates of deficits in pain-related affective meaning construction in patients with chronic pain disorder.

Objective Psychological and neural mechanisms of the affective dimension of pain are known to be disturbed in patients with chronic pain disorder. The aim of this functional magnetic resonance imaging study was to assess the neurofunctional and behavioral measures underlying the ability to construct pain-related affective meaning in a painful situation by comparing 21 clinically and psychometrically well-characterized patients with persistent non-nociceptive somatoform pain with 19 healthy controls. Methods The functional magnetic resonance imaging task involved viewing pictures depicting human hands and feet in different painful and nonpainful situations. Participants were asked to estimate the perceived pain intensity. These data were correlated with behavioral measures of depression, alexithymia, and general cognitive and emotional empathy. Results In a hypothesis-driven region-of-interest analysis, the healthy control group exhibited greater activation of the left perigenual anterior cingulate cortex than patients with pain (Montreal Neurological Institute coordinates (x y z) = −8 38 0; cluster extent = 54 voxels; T = 4.28; p = .006 corrected for multiple comparisons at cluster level). No group differences in the activation of the anterior insular cortex were found. Scores on self-assessment instruments (Beck Depression Inventory I, Interpersonal Reactivity Index, and 20-item Toronto Alexithymia Scale) did not influence neuroimaging results. Conclusions Our results suggest that patients with chronic medically unexplained pain have an altered neural pain perception process owing to decreased activation of empathetic-affective networks, which we interpret as a deficit in pain-related affective meaning construction. These findings may lead to a more specific and detailed neurobiological understanding of the clinical impression of disturbed affect in patients with chronic pain disorder.

Activation of CRH receptor type 1 expressed on glutamatergic neurons increases excitability of CA1 pyramidal neurons by the modulation of voltage-gated ion channels.

Corticotropin-releasing hormone (CRH) plays an important role in a substantial number of patients with stress-related mental disorders, such as anxiety disorders and depression. CRH has been shown to increase neuronal excitability in the hippocampus, but the underlying mechanisms are poorly understood. The effects of CRH on neuronal excitability were investigated in acute hippocampal brain slices. Population spikes (PS) and field excitatory postsynaptic potentials (fEPSP) were evoked by stimulating Schaffer-collaterals and recorded simultaneously from the somatic and dendritic region of CA1 pyramidal neurons. CRH was found to increase PS amplitudes (mean ± Standard error of the mean; 231.8 ± 31.2% of control; n = 10) while neither affecting fEPSPs (104.3 ± 4.2%; n = 10) nor long-term potentiation (LTP). However, when Schaffer-collaterals were excited via action potentials (APs) generated by stimulation of CA3 pyramidal neurons, CRH increased fEPSP amplitudes (119.8 ± 3.6%; n = 8) and the magnitude of LTP in the CA1 region. Experiments in slices from transgenic mice revealed that the effect on PS amplitude is mediated exclusively by CRH receptor 1 (CRHR1) expressed on glutamatergic neurons. The effects of CRH on PS were dependent on phosphatase-2B, L- and T-type calcium channels and voltage-gated potassium channels but independent on intracellular Ca2+-elevation. In patch-clamp experiments, CRH increased the frequency and decay times of APs and decreased currents through A-type and delayed-rectifier potassium channels. These results suggest that CRH does not affect synaptic transmission per se, but modulates voltage-gated ion currents important for the generation of APs and hence elevates by this route overall neuronal activity.

The grapes of war. Somatoform pain disorder and history of early war traumatization in older people.

Persistent pain is not a normal part of aging. Nevertheless, many older patients have long-lasting, more or less medically unexplained pain symptoms and, consequently, are often severely disabled, incur high health care costs, and have high comorbidity rates. Moreover, the effects of early traumatization, especially due to wars, and even below the level of posttraumatic stress disorder (PTSD) are apparent. However, the developmental and neurobiological underpinnings of somatoform pain disorder, especially in pain-prone elderly patients, and its correlations with a history of war traumatization even decades after the incident remain unclear. Furthermore, a management strategy for this disorder tailored to older people and their special needs is lacking. Adequate therapeutic regimens such as adjusted psychotherapeutic procedures for elderly patients can only be promoted through a better understanding of the neurobiological and biographical underpinnings of this still controversial disorder.ZusammenfassungAnhaltende Schmerzen sind kein normaler Bestandteil des Alterns. Dennoch haben viele ältere Patienten dauerhaft eine mehr oder weniger medizinisch nicht erklärbare Schmerzsymptomatik. Sie sind damit oft schwer beeinträchtigt, verursachen hohe Kosten im Gesundheitswesen und zeigen eine hohe Komorbiditätsrate. Auch sind die Folgen früher Traumatisierungen, insbesondere durch Kriege und sogar unterhalb der Ausprägung einer posttraumatischen Belastungsstörung (PTSD), offensichtlich. Jedoch bleiben die Entstehungs- und neurobiologischen Grundlagen der somatoformen Schmerzstörung, vor allem in schmerzgeneigten, älteren Patienten, und ihre Zusammenhänge mit einer Vorgeschichte von Kriegstraumatisierung – sogar Jahrzehnte nach dem Ereignis – unklar. Darüber hinaus fehlt für diese Erkrankung eine Behandlungsstrategie, die auf ältere Menschen und ihre besonderen Bedürfnisse zugeschnitten wäre. Adäquates therapeutisches Vorgehen, wie angepasste psychotherapeutische Prozeduren für ältere Patienten, können nur durch ein besseres Verständnis der neurobiologischen und biographischen Grundlagen dieser nach wie vor kontroversen Störung gefördert werden.

Default mode network of the brain. Neurobiology and clinical significance

The resting state of the human brain is intrinsically organized by the so-called default mode network (DMN) which comprises cortical midline structure as well as lateral parietal and temporal areas. The activity of this system increases during self-oriented thinking, e.g. during a resting state but decreases during externally oriented attention and specific cognitive tasks. This review article provides a historical and methodological outline of the DMN model and describes its functional anatomy and putative functions. Based on the empirical literature the clinical implications of alterations of the DMN architecture and its role in various mental disorders are discussed.