Chronic Pelvic Pain Syndrome in Men is Associated with Reduction of Relative Gray Matter Volume in the Anterior Cingulate Cortex Compared to Healthy Controls

Although chronic pelvic pain syndrome impairs the life of millions of people worldwide, the exact pathomechanisms involved remain to be elucidated. As with other chronic pain syndromes, the central nervous system may have an important role in chronic pelvic pain syndrome. Thus, we assessed brain alterations associated with abnormal pain processing in patients with chronic pelvic pain syndrome.

Nerve Injury-Induced Neuropathic Pain Causes Disinhibition of the Anterior Cingulate Cortex

Neuropathic pain caused by peripheral nerve injury is a debilitating neurological condition of high clinical relevance. On the cellular level, the elevated pain sensitivity is induced by plasticity of neuronal function along the pain pathway. Changes in cortical areas involved in pain processing contribute to the development of neuropathic pain. Yet, it remains elusive which plasticity mechanisms occur in cortical circuits. We investigated the properties of neural networks in the anterior cingulate cortex (ACC), a brain region mediating affective responses to noxious stimuli. We performed multiple whole-cell recordings from neurons in layer 5 (L5) of the ACC of adult mice after chronic constriction injury of the sciatic nerve of the left hindpaw and observed a striking loss of connections between excitatory and inhibitory neurons in both directions. In contrast, no significant changes in synaptic efficacy in the remaining connected pairs were found. These changes were reflected on the network level by a decrease in the mEPSC and mIPSC frequency. Additionally, nerve injury resulted in a potentiation of the intrinsic excitability of pyramidal neurons, whereas the cellular properties of interneurons were unchanged. Our set of experimental parameters allowed constructing a neuronal network model of L5 in the ACC, revealing that the modification of inhibitory connectivity had the most profound effect on increased network activity. Thus, our combined experimental and modeling approach suggests that cortical disinhibition is a fundamental pathological modification associated with peripheral nerve damage. These changes at the cortical network level might therefore contribute to the neuropathic pain condition.

Prefrontal Thinning Affects Functional Connectivity and Regional Homogeneity of the Anterior Cingulate Cortex in Depression

Major depressive disorder (MDD) is associated with structural and functional alterations in the prefrontal cortex (PFC) and anterior cingulate cortex (ACC). Enhanced ACC activity at rest (measured using various imaging methodologies) is found in treatment-responsive patients and is hypothesized to bolster treatment response by fostering adaptive rumination. However, whether structural changes influence functional coupling between fronto-cingulate regions and ACC regional homogeneity (ReHo) and whether these functional changes are related to levels of adaptive rumination and treatment response is still unclear. Cortical thickness and ReHo maps were calculated in 21 unmedicated depressed patients and 35 healthy controls. Regions with reduced cortical thickness defined the seeds for the subsequent functional connectivity (FC) analyses. Patients completed the Response Style Questionnaire, which provided a measure of adaptive rumination associated with better response to psychotherapy. Compared with controls, depressed patients showed thinning of the right anterior PFC, increased prefrontal connectivity with the supragenual ACC (suACC), and higher ReHo in the suACC. The suACC clusters of increased ReHo and FC spatially overlapped. In depressed patients, suACC ReHo scores positively correlated with PFC thickness and with FC strength. Moreover, stronger fronto-cingulate connectivity was related to higher levels of adaptive rumination. Greater suACC ReHo and connectivity with the right anterior PFC seem to foster adaptive forms of self-referential processing associated with better response to psychotherapy, whereas prefrontal thinning impairs the ability of depressed patients to engage the suACC during a major depressive episode. Bolstering the function of the suACC may represent a potential target for treatment.

The human vestibular cortex revealed by coordinate-based activation likelihood estimation meta-analysis.

The vestibular system contributes to the control of posture and eye movements and is also involved in various cognitive functions including spatial navigation and memory. These functions are subtended by projections to a vestibular cortex, whose exact location in the human brain is still a matter of debate (Lopez and Blanke, 2011). The vestibular cortex can be defined as the network of all cortical areas receiving inputs from the vestibular system, including areas where vestibular signals influence the processing of other sensory (e.g. somatosensory and visual) and motor signals. Previous neuroimaging studies used caloric vestibular stimulation (CVS), galvanic vestibular stimulation (GVS), and auditory stimulation (clicks and short-tone bursts) to activate the vestibular receptors and localize the vestibular cortex. However, these three methods differ regarding the receptors stimulated (otoliths, semicircular canals) and the concurrent activation of the tactile, thermal, nociceptive and auditory systems. To evaluate the convergence between these methods and provide a statistical analysis of the localization of the human vestibular cortex, we performed an activation likelihood estimation (ALE) meta-analysis of neuroimaging studies using CVS, GVS, and auditory stimuli. We analyzed a total of 352 activation foci reported in 16 studies carried out in a total of 192 healthy participants. The results reveal that the main regions activated by CVS, GVS, or auditory stimuli were located in the Sylvian fissure, insula, retroinsular cortex, fronto-parietal operculum, superior temporal gyrus, and cingulate cortex. Conjunction analysis indicated that regions showing convergence between two stimulation methods were located in the median (short gyrus III) and posterior (long gyrus IV) insula, parietal operculum and retroinsular cortex (Ri). The only area of convergence between all three methods of stimulation was located in Ri. The data indicate that Ri, parietal operculum and posterior insula are vestibular regions where afferents converge from otoliths and semicircular canals, and may thus be involved in the processing of signals informing about body rotations, translations and tilts. Results from the meta-analysis are in agreement with electrophysiological recordings in monkeys showing main vestibular projections in the transitional zone between Ri, the insular granular field (Ig), and SII.

[Chronic right-sided pain-associated nondermatomal somatosensory deficit following an accident]

We present the case of a 48-year old man who, eight years after an industrial accident, presents with chronic right-sided nondermatomal pain and hypaesthesia to heat and touch. During symmetric peripheral touch functional magnetic resonance imaging revealed hypometabolism in the left thalamus, somatosensory cortex, and anterior cingulate cortex. Pain-associated nondermatomal somatosensory deficits (NDSDs) localizing to one side of the body are a frequent clinical entity, which are often triggered by an accident. The tendency of NDSDs to extend to adjunct ipsilateral body parts and to become chronic points to maladaptive adjustment of pain-processing areas in the central nervous system. Psychological stress prior to or around the triggering event seems an important risk factor for NDSDs.

Resting state cerebral blood flow and objective motor activity reveal basal ganglia dysfunction in schizophrenia

Reduced motor activity has been reported in schizophrenia and was associated with subtype, psychopathology and medication. Still, little is known about the neurobiology of motor retardation. To identify neural correlates of motor activity, resting state cerebral blood flow (CBF) was correlated with objective motor activity of the same day. Participants comprised 11 schizophrenia patients and 14 controls who underwent magnetic resonance imaging with arterial spin labeling and wrist actigraphy. Patients had reduced activity levels and reduced perfusion of the left parahippocampal gyrus, left middle temporal gyrus, right thalamus, and right prefrontal cortex. In controls, but not in schizophrenia, CBF was correlated with activity in the right thalamic ventral anterior (VA) nucleus, a key module within basal ganglia-cortical motor circuits. In contrast, only in schizophrenia patients positive correlations of CBF and motor activity were found in bilateral prefrontal areas and in the right rostral cingulate motor area (rCMA). Grey matter volume correlated with motor activity only in the left posterior cingulate cortex of the patients. The findings suggest that basal ganglia motor control is impaired in schizophrenia. In addition, CBF of cortical areas critical for motor control was associated with volitional motor behavior, which may be a compensatory mechanism for basal ganglia dysfunction.

Semantic memory involvement in the default mode network: a functional neuroimaging study using independent component analysis

The Default Mode Network (DMN) is a higher order functional neural network that displays activation during passive rest and deactivation during many types of cognitive tasks. Accordingly, the DMN is viewed to represent the neural correlate of internally-generated self-referential cognition. This hypothesis implies that the DMN requires the involvement of cognitive processes, like declarative memory. The present study thus examines the spatial and functional convergence of the DMN and the semantic memory system. Using an active block-design functional Magnetic Resonance Imaging (fMRI) paradigm and Independent Component Analysis (ICA), we trace the DMN and fMRI signal changes evoked by semantic, phonological and perceptual decision tasks upon visually-presented words. Our findings show less deactivation during semantic compared to the two non-semantic tasks for the entire DMN unit and within left-hemispheric DMN regions, i.e., the dorsal medial prefrontal cortex, the anterior cingulate cortex, the retrosplenial cortex, the angular gyrus, the middle temporal gyrus and the anterior temporal region, as well as the right cerebellum. These results demonstrate that well-known semantic regions are spatially and functionally involved in the DMN. The present study further supports the hypothesis of the DMN as an internal mentation system that involves declarative memory functions.

Electroencephalographic topography measures of experienced utility

Economic theory distinguishes two concepts of utility: decision utility, objectively quantifiable by choices, and experienced utility, referring to the satisfaction by an obtainment. To date, experienced utility is typically measured with subjective ratings. This study intended to quantify experienced utility by global levels of neuronal activity. Neuronal activity was measured by means of electroencephalographic (EEG) responses to gain and omission of graded monetary rewards at the level of the EEG topography in human subjects. A novel analysis approach allowed approximating psychophysiological value functions for the experienced utility of monetary rewards. In addition, we identified the time windows of the event-related potentials (ERP) and the respective intracortical sources, in which variations in neuronal activity were significantly related to the value or valence of outcomes. Results indicate that value functions of experienced utility and regret disproportionally increase with monetary value, and thus contradict the compressing value functions of decision utility. The temporal pattern of outcome evaluation suggests an initial (∼250 ms) coarse evaluation regarding the valence, concurrent with a finer-grained evaluation of the value of gained rewards, whereas the evaluation of the value of omitted rewards emerges later. We hypothesize that this temporal double dissociation is explained by reward prediction errors. Finally, a late, yet unreported, reward-sensitive ERP topography (∼500 ms) was identified. The sources of these topographical covariations are estimated in the ventromedial prefrontal cortex, the medial frontal gyrus, the anterior and posterior cingulate cortex and the hippocampus/amygdala. The results provide important new evidence regarding “how,” “when,” and “where” the brain evaluates outcomes with different hedonic impact.

Reduced Cerebral Blood Flow Within the Default-Mode Network and Within Total Gray Matter in Major Depression

The default-mode network (DMN) was shown to have aberrant blood oxygenation-level-dependent (BOLD) activity in major depressive disorder (MDD). While BOLD is a relative measure of neural activity, cerebral blood flow (CBF) is an absolute measure. Resting-state CBF alterations have been reported in MDD. However, the association of baseline CBF and CBF fluctuations is unclear in MDD. Therefore, the aim was to investigate the CBF within the DMN in MDD, applying a strictly data-driven approach. In 22 MDD patients and 22 matched healthy controls, CBF was acquired using arterial spin labeling (ASL) at rest. A concatenated independent component analysis was performed to identify the DMN within the ASL data. The perfusion of the DMN and its nodes was quantified and compared between groups. The DMN was identified in both groups with high spatial similarity. Absolute CBF values within the DMN were reduced in MDD patients (p<0.001). However, after controlling for whole-brain gray matter CBF and age, the group difference vanished. In patients, depression severity was correlated with reduced perfusion in the DMN in the posterior cingulate cortex and the right inferior parietal lobe. Hypoperfusion within the DMN in MDD is not specific to the DMN. Still, depression severity was linked to DMN node perfusion, supporting a role of the DMN in depression pathobiology. The finding has implications for the interpretation of BOLD functional magnetic resonance imaging data in MDD.

Cortico-cortical white matter motor pathway microstructure is related to psychomotor retardation in major depressive disorder

Alterations of brain structure and function have been associated with psychomotor retardation in major depressive disorder (MDD). However, the association of motor behaviour and white matter integrity of motor pathways in MDD is unclear. The aim of the present study was to first investigate structural connectivity of white matter motor pathways in MDD. Second, we explore the relation of objectively measured motor activity and white matter integrity of motor pathways in MDD. Therefore, 21 patients with MDD and 21 healthy controls matched for age, gender, education and body mass index underwent diffusion tensor imaging and 24 hour actigraphy (measure of the activity level) the same day. Applying a probabilistic fibre tracking approach we extracted connection pathways between the dorsolateral prefrontal cortex (dlPFC), the rostral anterior cingulate cortex (rACC), the pre-supplementary motor area (pre-SMA), the SMA-proper, the primary motor cortex (M1), the caudate nucleus, the putamen, the pallidum and the thalamus. Patients had lower activity levels and demonstrated increased mean diffusivity (MD) in pathways linking left pre-SMA and SMA-proper, and right SMA-proper and M1. Exploratory analyses point to a positive association of activity level and mean-fractional anisotropy in the right rACC-pre-SMA connection in MDD. Only MDD patients with low activity levels had a negative linear association of activity level and mean-MD in the left dlPFC-pre-SMA connection. Our results point to structural alterations of cortico-cortical white matter motor pathways in MDD. Altered white matter organisation of rACC-pre-SMA and dlPFC-pre-SMA pathways may contribute to movement initiation in MDD.

Altered cortico-basal ganglia motor pathways reflect reduced volitional motor activity in schizophrenia

Little is known about the neurobiology of hypokinesia in schizophrenia. Therefore, the aim of this study was to investigate alterations of white matter motor pathways in schizophrenia and to relate our findings to objectively measured motor activity. We examined 21 schizophrenia patients and 21 healthy controls using diffusion tensor imaging and actigraphy. We applied a probabilistic fibre tracking approach to investigate pathways connecting the dorsolateral prefrontal cortex (dlPFC), the rostral anterior cingulate cortex (rACC), the pre-supplementary motor area (pre-SMA), the supplementary motor area proper (SMA-proper), the primary motor cortex (M1), the caudate nucleus, the striatum, the pallidum and the thalamus. Schizophrenia patients had lower activity levels than controls. In schizophrenia we found higher probability indices forming part of a bundle of interest (PIBI) in pathways connecting rACC, pre-SMA and SMA-proper as well as in pathways connecting M1 and pre-SMA with caudate nucleus, putamen, pallidum and thalamus and a reduced spatial extension of motor pathways in schizophrenia. There was a positive correlation between PIBI and activity level in the right pre-SMA-pallidum and the left M1-thalamus connection in healthy controls, and in the left pre-SMA-SMA-proper pathway in schizophrenia. Our results point to reduced volitional motor activity and altered motor pathway organisation in schizophrenia. The identified associations between the amount of movement and structural connectivity of motor pathways suggest dysfunction of cortico-basal ganglia pathways in the pathophysiology of hypokinesia in schizophrenia. Schizophrenia patients may use cortical pathways involving the supplementary motor area to compensate for basal ganglia dysfunction.

Cell-type specific alterations of cortical interneurons in schizophrenic patients

In the human brain, cortical GABAergic interneurons represent an important population of local circuit neurons responsible for the intrinsic modulation of neuronal information and have been supposed to be involved in the pathophysiology of schizophrenia. We conducted a quantitative study on the differentiated three-dimensional morphological structure of two types of parvalbumin-immunoreactive interneurons in the anterior cingulate cortex (ACC) of schizophrenic patients versus controls. While type A interneurons ('small bipolar cells') showed a significant reduction of their soma size in schizophrenics, type B interneurons ('small multipolar cells') of schizophrenic patients exhibited a marked decrease in the extent of their dendritic system. These results further support the assumption of a considerable significance of the ACC, an important limbic relay centre, for the etiopathogenesis of schizophrenic psychoses.

Nondermatomal somatosensory deficits in patients with chronic pain disorder: clinical findings and hypometabolic pattern in FDG-PET

Patients with chronic pain disorders often show somatosensory disturbances that are considered to be functional. This paper aims at a more precise clinical description and at a documentation of functional neuroimaging correlates of this phenomenon. We examined 30 consecutive patients with unilaterally accentuated chronic pain not explained by persistent peripheral tissue damage and ipsilateral somatosensory disturbances including upper and lower extremities and trunk. The patients were assessed clinically and with conventional brain CT or MRI scan. In the last 11 patients functional neuroimaging was carried out (18-fluordeoxyglucose positron emission tomography=FDG-PET). Depressive symptoms were assessed with the Hamilton depression scale (HAMD-17) and pain intensity was rated with a visual analogue scale for pain (VAS). All patients suffered from mild to moderate depressive symptoms. All patients had experienced a prolonged antecedent phase of severe emotional distress; most of them remembered a "trigger episode of somatic pain" on the affected side. Somatosensory deficits were a replicable hyposensitivity to touch and heat perception of nondermatomal distribution. Conventional imaging procedures (brain CT or MRI scans) showed no structural changes. However, in 11 patients functional imaging with FDG-PET showed a significant hypometabolic pattern of changes in cortical and subcortical areas, mainly in the post-central gyrus, posterior insula, putamen, and anterior cingulate cortex. In summary, pain-related nondermatomal somatosensory deficits (NDSDs) are a phenomenon involving biological as well as psychosocial factors with replicable neuroperceptive clinical findings and a complex neurodysfunctional pattern in the FDG-PET.

Hemispheric lateralization of the corticostriatal glutamatergic system in the rat

Little is known about hemispheric lateralization of subcortical structures. Here, we show a higher expression of the subunit NR2A of the NMDA receptor mRNA in the striatum and of vGluT1 mRNA in the cingulate cortex, in the left hemisphere compared to the right one. This suggests a lateralization of the glutamatergic cortico-subcortical system, at the level of postsynaptic receptors as well as at the level of corticostriatal projections. Such lateralization could play a role in asymmetric diseases like Parkinson's disease.