Treatment of depression with low-strength transcranial pulsed electromagnetic fields: A mechanistic point of view.

BACKGROUND: Mood disorders constitute a high burden for both patients and society. Notwithstanding the large arsenal of available treatment options, a considerable group of patients does not remit on current antidepressant treatment. There is an urgent need to develop alternative treatment strategies. Recently, low-strength transcranial pulsed electromagnetic field (tPEMF) stimulation has been purported as a promising strategy for such treatment-resistant depression (TRD). The mode of action of this new technique is however largely unknown. METHODS: We searched PubMed for literature reports on the effects of tPEMF and for information regarding its working mechanism and biological substrate. RESULTS: Most studies more or less connect with the major hypotheses of depression and concern the effects of tPEMF on brain metabolism, neuronal connectivity, brain plasticity, and the immune system. Relatively few studies paid attention to the possible chronobiologic effects of electromagnetic fields. LIMITATIONS: We reviewed the literature of a new and still developing field. Some of the reports involved translational studies, which inevitably limits the reach of the conclusions. CONCLUSION: Weak magnetic fields influence divergent neurobiological processes. The antidepressant effect of tPEMF may be specifically attributable to its effects on local brain activity and connectivity.

Herniation of the colon through the foramen of Winslow-A case report.

INTRODUCTION: Herniation of the bowel through the foramen of Winslow is a rare condition presenting with acute abdominal pain. Diagnostic delay often results in high morbidity and mortality. CASE PRESENTATION: A patient presented with right sided acute abdominal pain. Computed tomography showed herniation of the ascending colon through the foramen of Winslow which could be reversed laparoscopically without the need for bowel resection. There were no postoperative complications and no recurrences have occurred to date. DISCUSSION: Bowel herniation through the foramen of Winslow is very rare, comprising only 8% of all internal herniations. Historically, the majority of cases was diagnosed intra-operatively and bowel resection was necessary because of ischemia. With the introduction of computed tomography, the diagnosis can be made earlier, possibly resulting in a lower morbidity and mortality rate. CONCLUSION: Herniation through the foramen of Winslow is a rare condition. Patients will present with sudden onset abdominal pain. Early imaging helps to recognize the diagnosis and could prevent bowel ischemia.

[Brain activation as endophenotype for investigating genetics of depression]. / Hersenactiviteit als endofenotype voor het genetisch onderzoek naar depressie.

BACKGROUND: Many factors are involved in the pathogenesis of depression. This article provides an overview of the results given in the thesis entitled 'Linking Depression', in which some putative underlying neurobiological and genetic mechanisms of depression are examined. AIM: To gain more insight in brain activity as endophenotype for depression. METHOD: As part of the Netherlands Study of Depression and Anxiety (nesda), 301 people, including patients with depression and/or anxiety and healthy volunteers, underwent functional magnetic resonance imaging (fmri) and genotyping. RESULTS: During the processing of negative emotions, patients with depression showed a pattern of heightened limbic activation but less prefrontal activation. The same pattern, but in reverse, was seen during the processing of positive emotions. We showed that the disc1, comt and npy genes were associated with brain activation patterns comparable to those seen in patients with depression. In addition, in cases of depression, there was a different kind of relationship between these genes and brain activation. CONCLUSION: Depression is characterised by the disturbed processing not only of negative emotions but also of positive emotions. In addition, the studies we describe contribute to our insight into the neurobiology of depression and relevant genetic influences because the results demonstrate that depression alters the relationship between genes and brain activation.

Amygdala activation and its functional connectivity during perception of emotional faces in social phobia and panic disorder.

Social phobia (SP) and panic disorder (PD) have been associated with aberrant amygdala responses to threat-related stimuli. The aim of the present study was to examine amygdala function and its connectivity with medial prefrontal cortex (mPFC) during emotional face perception in PD and SP, and the role of illness severity. Blood oxygen level dependent responses while perceiving emotional facial expressions were compared in 14 patients with PD, 17 patients with SP, 8 patients with comorbid PD and SP, and 16 healthy controls. We found that PD, but not SP, was associated with amygdala and lingual gyrus hypoactivation during perception of angry, fearful, happy and neutral faces, compared to healthy participants. No significant effect of PD and SP diagnoses was found on amygdala-mPFC connectivity. A positive correlation of anxiety symptom severity was found on amygdala-dorsal anterior cingulate and dorsal mPFC connectivity during perception of fearful faces. Amygdala hypoactivation suggests reduced responsiveness to positive and negative emotional faces in PD. Symptom severity, but not the presence of PD and SP diagnosis per se, explains most of the abnormalities in amygdala-mPFC connectivity during perception of fearful faces.

Motor behavior correlates with striatal [¹8F]-DOPA uptake in MPTP-lesioned primates.

The MPTP-lesioned monkey is considered as the best animal model for Parkinson's disease (PD). It has damage to dopaminergic cell groups and motor dysfunction similar to that seen in PD. Correlations between these two parameters have been described but there is a lack of formal statistical analyses on dopaminergic function as assessed by [(18)F]-F-DOPA PET and objectively rated motor behavior in longitudinal experiments. Eight rhesus monkeys received two MPTP infusions: first in one carotid artery, and after eight weeks in the other. Motor behavior and [(18)F]-F-DOPA uptake were measured at three stages: baseline, unilateral and bilateral. We correlated movement with radiotracer uptake across these three stages. MPTP caused the expected parkinsonian motor signs which were accompanied by lower radioactivity concentrations in the striatum. There were significant correlations between dopaminergic function and behavior. In conclusion, striatal [(18)F]-F-DOPA uptake correlates inversely with the severity of motor impairment in MPTP-lesioned non-human primates. Both behavioral scoring and [(18)F]-F-DOPA PET scans are useful and sensitive methods to monitor dopaminergic degeneration within subjects.

Spumiform basement membrane aberrations in the microvasculature of the midbrain periaqueductal gray region in hamster: rostro-caudal pathogenesis?

Spumiform basement membrane degeneration (sbmd) is a specific kind of aberration present in the capillaries of the midbrain periaqueductal gray (PAG) region of the senescent hamster. These capillaries, separated by the ependymal cell layer, are bordering the Sylvian cerebral aqueduct. The aqueduct, connecting the 3rd and 4th ventricle, may be crucial for local homeostatic as well as general autonomic functions of the PAG. Local pressure effects of the flowing and pulsating cerebrospinal fluid on the PAG-vasculature are probably different for the rostral 'entrance' and the caudal 'exit' of the aqueduct. In view of the different functions of the various divisions of the PAG, the frequency and extent of the aberrations in the rostral, intermediate and caudal dl/vlPAG-microvasculature could shed some light on the causal factors involved in the regional distribution of the particular microvascular aberrations found in the PAG during aging. In the present study we investigated the ultrastructure of capillaries in dorsal and ventral subdivisions of anterior and posterior regions of the PAG of young and old female Syrian hamsters. Sbmds were classified into four stages of spumiform severity and for each stage the frequency was determined in the rostral PAG, at two levels in the intermediate PAG and in a dorsal and a ventral part of the caudal PAG. Results of our quantitative studies showed that in aged hamster PAG various stages of sbmd were present in 91.6 ± 0.6% of all capillaries. No clear evidence was found for regional differentiation between rostral, intermediate and caudal parts of the PAG. Next to sbmd, capillary split basement membrane (sbm) and vacuolization were common features at all five PAG locations. 84.3 ± 2.3% of all screened PAG capillaries displayed sbm. In agreement with our previous findings, several other types of microvascular aberrations were observed in addition to general aspects of aging and some ependymal structural peculiarities. We conclude that the presence of various forms of sbmds in the PAG of senescent hamsters is a phenomenon that appears to be specific to the PAG region, but causal factors for this type of capillary degeneration remain unclear. Sbmds in the PAG may have serious consequences not only for blood-brain barrier functioning, but also for vascular perfusion and blood supply with eventually serious consequences for adequate regulation of the autonomic and motor control functions of the PAG region.

Neural correlates of perception of emotional facial expressions in out-patients with mild-to-moderate depression and anxiety. A multicenter fMRI study.

BACKGROUND: Depression has been associated with limbic hyperactivation and frontal hypoactivation in response to negative facial stimuli. Anxiety disorders have also been associated with increased activation of emotional structures such as the amygdala and insula. This study examined to what extent activation of brain regions involved in perception of emotional faces is specific to depression and anxiety disorders in a large community-based sample of out-patients. METHOD: An event-related functional magnetic resonance imaging (fMRI) paradigm was used including angry, fearful, sad, happy and neutral facial expressions. One hundred and eighty-two out-patients (59 depressed, 57 anxiety and 66 co-morbid depression-anxiety) and 56 healthy controls selected from the Netherlands Study of Depression and Anxiety (NESDA) were included in the present study. Whole-brain analyses were conducted. The temporal profile of amygdala activation was also investigated. RESULTS: Facial expressions activated the amygdala and fusiform gyrus in depressed patients with or without anxiety and in healthy controls, relative to scrambled faces, but this was less evident in patients with anxiety disorders. The response shape of the amygdala did not differ between groups. Depressed patients showed dorsolateral prefrontal cortex (PFC) hyperactivation in response to happy faces compared to healthy controls. CONCLUSIONS: We suggest that stronger frontal activation to happy faces in depressed patients may reflect increased demands on effortful emotion regulation processes triggered by mood-incongruent stimuli. The lack of strong differences in neural activation to negative emotional faces, relative to healthy controls, may be characteristic of the mild-to-moderate severity of illness in this sample and may be indicative of a certain cognitive-emotional processing reserve.

11C-verapamil to assess P-gp function in human brain during aging, depression and neurodegenerative disease.

P-glycoprotein (P-gp) at the blood-brain barrier (BBB) functions as an active efflux pump by extruding a wide range of substrates from the brain. This is important for maintaining loco-regional homeostasis and for protecting the brain against blood-borne toxic substances. Altered P-gp function seems to be involved in the pathophysiology of neurodegenerative disease and various neurological and psychiatric disorders. Positron emission tomography (PET) with the radiotracer (11)C-verapamil (VPM-PET) is a validated technique allowing measurement of P-gp function at the human BBB. In this review, we highlight changes of P-gp function, as measured with VPM-PET, in aging and in the pathogenesis and progression of neurodegenerative disease, as well as their role in depressive disorders.

Estrous cycle-dependent neural plasticity in the caudal brainstem in the female golden hamster: ultrastructural and immunocytochemical studies of axo-dendritic relationships and dynamic remodeling.

UNLABELLED: During the short four-day estrous cycle of the female hamster various behavioral (lordosis, vocalization and aggression) and autonomic adaptations occur. Presumably, these changes are under ovarian control. Recently, we described a distinct estrogen receptor-alpha immunoreactive (ER-alpha-IR) cell group, now called nucleus para-retroambiguus (NPRA), in the caudal ventrolateral medulla (Gerrits et al., 2008). Neurons of this group project to the ipsilateral intermediolateral cell column in the thoracic and upper lumbar cord. Clearly, the NPRA is part of an estrogen-sensitive neuronal network and the same applies to the region containing the commissural part of the solitary tract nucleus (NTScom) and the A2 group, here called NTScom/A2. Estrogen is known to modulate neuronal ultrastructure in various brain areas and spinal cord, but not in the caudal brainstem. Because we assumed that the NPRA plays a role in estrous cycle related adaptations, we hypothesized the occurrence of plasticity in this nucleus. In the present study we examined morphological changes of axo-dendritic relationships in NPRA and NTScom/A2 in estrous, diestrous and ovariectomized (OVX) hamsters, using immuno-electron microscopy and the 1D5 anti-ER-alpha antibody. Ultrastructural analysis revealed that the ratio "axon terminals surface/dendrite surface" was significantly increased in both the NPRA and NTScom/A2 during the estrous phase compared to the OVX and diestrous conditions. Remodeling of axon terminals due to axonal sprouting into large terminal fields filled up with pleomorphic vesicles resulted in contacts with more dendrites, and was the main cause for the "axonal terminal-dendritic-ratio" shift. IN CONCLUSION: Estrous cycle-induced axonal and dendritic plasticity is present in the NPRA, and in the NTScom/A2 group. Our findings support our hypothesis that estrogen-sensitive neuronal networks in the caudal brainstem display structural plasticity, probably to modulate steroid hormone dependent behaviors or autonomic adaptations.

Decreased blood-brain barrier P-glycoprotein function in the progression of Parkinson's disease, PSP and MSA.

Decreased blood-brain barrier (BBB) efflux function of the P-glycoprotein (P-gp) transport system could facilitate the accumulation of toxic compounds in the brain, increasing the risk of neurodegenerative pathology such as Parkinson's disease (PD). This study investigated in vivo BBB P-gp function in patients with parkinsonian neurodegenerative syndromes, using [11C]-verapamil PET in PD, PSP and MSA patients. Regional differences in distribution volume were studied using SPM with higher uptake interpreted as reduced P-gp function. Advanced PD patients and PSP patients had increased [11C]-verapamil uptake in frontal white matter regions compared to controls; while de novo PD patients showed lower uptake in midbrain and frontal regions. PSP and MSA patients had increased uptake in the basal ganglia. Decreased BBB P-gp function seems a late event in neurodegenerative disorders, and could enhance continuous neurodegeneration. Lower [11C]-verapamil uptake in midbrain and frontal regions of de novo PD patients could indicate a regional up-regulation of P-gp function.

Assessment of methylphenidate-induced changes in binding of continuously infused [(11)C]-raclopride in healthy human subjects: correlation with subjective effects.

RATIONALE: The dopaminergic system has been implicated in the pathogenesis and treatment of a variety of neuropsychiatric disorders. It has been shown that information on endogenous dopamine (DA) release can be obtained noninvasively by combining positron emission tomography with a dopaminergic challenge. This approach is based on the assumption that an injected radiolabeled ligand competes with the neurotransmitter for the same receptor. Increases in DA release will therefore result in a decreased binding of the radioligand. OBJECTIVES: We investigated the effect of the DA reuptake blocker methylphenidate (MP) on the binding of the D(2) receptor ligand [(11)C]-raclopride (RAC). METHODS: The effect of a 0.25 mg/kg intravenous dose of MP was studied in six healthy volunteers. RAC was administered as a bolus followed by constant infusion, and subjective effects were assessed using verbal rating scales. RESULTS: Control scans without MP administration showed that the mean RAC binding reached stable values approximately 30 min after start of the infusion. MP administration induced a 24% decrease in RAC binding in the total striatum. Correlations were found between the MP-induced change in euphoria and the percent change in binding potential (DeltaBP) in the dorsal striatum and between baseline anxiety and DeltaBP in the dorsal and middle striatum. We also found a negative correlation between baseline BP in the dorsal striatum and change in euphoria. CONCLUSIONS: Our results comply with previous findings, indicating the feasibility of the bolus infusion design combined with a relatively low MP dose to study dopaminergic (dys)function.

Development of an inexpensive, low attenuation styrofoam primate chair for use in a PET scanner.

Pharmacokinetic modelling of radiotracers for positron emission tomography (PET) imaging of neuroreceptors can be performed with time-activity data for brain and blood. We aimed to develop an alternative to withdrawal of arterial blood samples for acquisition of a blood curve. A supportive primate chair was constructed out of styrofoam and fixed to the head portion of the bed of a PET scanner. A lightly anaesthetised rhesus monkey was positioned in the chair in a sitting position and injected with the radiotracer. The styrofoam chair provided sufficient support for the monkey. The presence of the chair in the PET scanner caused negligible attenuation of radiation, allowing simultaneous acquisition of dynamic data from the subject's brain and heart. We conclude that a styrofoam primate chair is an ideal tool to measure blood and brain data from a rhesus monkey with PET. Invasiveness to the animal is reduced, as well as experimenter time.

[Conservative treatment of a spontaneous splenic rupture in a patient with infectious mononucleosis]. / Conservatieve behandeling van een spontane miltruptuur bij een patiënt met de ziekte van Pfeiffer.

A 30-year-old man with flu-like symptoms for several weeks presented at the emergency room with pain in the left upper abdomen. There was no history of trauma. The patient had a spontaneous rupture of the spleen due to mononucleosis infectiosa. He was successfully treated with conservative management during a 7-day period of hospitalisation. Spontaneous splenic rupture is a rare but potentially lethal complication of infectious mononucleosis. Alarming symptoms are left upper abdominal pain, worsening during inspiration, and haemodynamic instability. Although splenectomy is the accepted treatment for haemodynamically unstable patients, some patients, may be adequately treated with conservative management. They should be observed during the critical phase and must comply to a period of restricted physical activity after they are discharged from the hospital. There is no consensus about the length or content of this restriction period.

Bandwidth effects on children's perception of the inflectional morpheme /s/: acoustical measurements, auditory detection, and clarity rating.

The goal of this study was to examine developmental effects in auditory perception of word-final /s/ in inflectional morpheme contexts as a function of high-frequency (HF) bandwidth. Such developmental effects may support the use of hearing aids with extended bandwidths in young children with impaired hearing. The first part of the study consisted of acoustical measurements on word-initial /s/ and inflectional morpheme /s/ in sentences recorded from a male speaker. For this speaker, recordings of inflectional morpheme /s/ on average were approximately 50 ms shorter and about 5 dB lower in level than word-initial /s/ sounds. They also had a lower spectral center of gravity, but not a higher coefficient of kurtosis. The second part consisted of measurements of psychometric functions relating detection of the inflectional morpheme /s/ sounds to HF bandwidth in normally hearing 5-, 7-, and 10-year-old children and adults. In speech-shaped noise, significant main effects of age were found for detection as a function of bandwidth for both the 30- and 10-dB signal-to-noise ratio (SNR) condition, although there was no interaction between age and SNR condition. The third part consisted of subjective clarity rating as a function of HF bandwidth for the same speech stimuli used in the second part. No differences were found between age groups in the shape of the clarity rating functions, but differences were found in the rating variance. No systematic effects of the spectral composition of inflectional morpheme /s/ sounds on either detection or clarity rating were found. The higher detection thresholds and larger clarity rating variances for the youngest participants support the use of extended high-frequency bandwidths for young children with impaired hearing. The extent to which the potential benefit of extended bandwidths is affected by hearing impairment in this population, however, deserves further investigation.

The relation between stimulus context, speech audibility, and perception for normal-hearing and hearing-impaired children.

In this study, the influence of stimulus context and audibility on sentence recognition was assessed in 60 normal-hearing children, 23 hearing-impaired children, and 20 normal-hearing adults. Performance-intensity (PI) functions were obtained for 60 semantically correct and 60 semantically anomalous sentences. For each participant, an audibility index (AI) was calculated at each presentation level, and a logistic function was fitted to rau-transformed percent-correct values to estimate the SPL and AI required to achieve 70% performance. For both types of sentences, there was a systematic age-related shift in the PI functions, suggesting that young children require a higher AI to achieve performance equivalent to that of adults. Improvement in performance with the addition of semantic context was statistically significant only for the normal-hearing 5-year-olds and adults. Data from the hearing-impaired children showed age-related trends that were similar to those of the normal-hearing children, with the majority of individual data falling within the 5th and 95th percentile of normal. The implications of these findings in terms of hearing-aid fitting strategies for young children are discussed.

Influence of peptide CRF receptor antagonists upon the behavioural effects of human/rat CRF.

The effects of the corticotropin-releasing factor (CRF) receptor antagonists, alpha-helical CRF-(9-41), [D-Phe12,Nle21,38, CalphaMe-Leu37]humanCRF-(12-41) (D-PheCRF-(12-41)) and astressin ([cyclo(30-33)[D-Phe12,Nle21,38,Glu30,Lys33]h umanCRF-(12-41) upon hypophagic and motor activation response to human/ratCRF (h/rCRF) were investigated. All three antagonists (100 microg intracerebroventricular (i.c.v.)) blocked the effects of h/rCRF (1 microg i.c.v.) upon food intake and body weight change in food-deprived rats. In contrast, alpha-helical CRF-(9-41) and astressin (both at 100 microg i.c.v., but not lower doses), but not D-PheCRF-(12-41) (up to 100 microg i.c.v.), blocked h/rCRF (0.3 microg i.c.v.)-induced motor activation in rats in a familiar environment. The ability of D-PheCRF-(12-41) to block CRF-induced hypophagia, but not motor activation, suggests a selective action of this antagonist upon the behavioural effects of centrally administered h/rCRF.

Changes in hippocampal theta following intrahippocampal corticotropin-releasing hormone (CRH) infusions in the rat.

Hippocampal theta activity is a large amplitude, sinusoidal wave that occurs during attentive immobility and exploratory behaviour in the rat, and it is thought to be involved in memory formation. Recent reports suggest that corticotropin-releasing hormone (CRH) has pro-mnemonic effects in rodents. Because memory-enhancing substances/manipulations generally alter either theta frequencies or amplitudes, these variables were monitored in urethane-anaesthetised rats following intrahippocampal infusions of CRH. Adult male, Lister hooded rats were implanted with a hippocampal recording electrode and a guide cannula, both aimed at the dentate gyrus. When CRH was infused into the hippocampus, the main change in the hippocampal EEG was a slow onset increase in the amplitude of spontaneous theta and, paradoxically, a significant decrease in the amount of time spent displaying theta. These data suggest that CRH has the ability to modulate ongoing hippocampal theta, but, considering the slow effect, the involvement of hippocampal CRH receptors is suspect. Regardless of locus, the described electrophysiological changes suggest that hippocampal cholinergic systems may play a role in the memory-enhancing effects of CRH.

Psychoacoustical evaluation of PSOLA. II. Double-formant stimuli and the role of vocal perturbation.

This article presents the results of listening experiments and psychoacoustical modeling aimed at evaluating the pitch synchronous overlap-and-add (PSOLA) technique. This technique can be used for simultaneous modification of pitch and duration of natural speech, using simple and efficient time-domain operations on the speech waveform. The first set of experiments tested the ability of subjects to discriminate double-formant stimuli, modified in fundamental frequency using PSOLA, from unmodified stimuli. Of the potential auditory discrimination cues induced by PSOLA, cues from the first formant were found to generally dominate discrimination performance. In the second set of experiments the influence of vocal perturbation, i.e., jitter and shimmer, on discriminability of PSOLA-modified single-formant stimuli was determined. The data show that discriminability deteriorates at most modestly in the presence of jitter and shimmer. With the exception of a few conditions, the trends in these data could be replicated by either using a modulation-discrimination or an intensity-discrimination model, dependent on the formant frequency. As a baseline experiment detection thresholds for jitter and shimmer were measured. Thresholds for jitter could be replicated by using either the modulation-discrimination or the intensity-discrimination model, dependent on the (mean) fundamental frequency of stimuli. The thresholds for shimmer could be accurately predicted for stimuli with a 250-Hz fundamental, but less accurately in the case of a 100-Hz fundamental.

Acute rise in corticosterone facilitates 5-HT(1A) receptor-mediated behavioural responses.

Corticosterone influences 5-HT1A receptor-mediated responses in the rat hippocampus in vitro: activation of the high affinity mineralocorticoid receptor suppresses 5-HT1A receptor-mediated hyperpolarization, while subsequent activation of lower affinity glucocorticoid receptors enhances the effect of 5-HT. We have tested whether a similar effect of corticosterone exists in vivo. In intact rats, a systemic injection of the specific 5-HT1A receptor agonist, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), led to increased locomotion and to a less persistent search strategy in the free swim trial of the Morris water maze test. Adrenalectomized rats with a corticosterone-pellet implanted as replacement received an injection of vehicle (predominant mineralocorticoid receptor occupation) or a high dose of corticosterone (both corticosteroid receptor types occupied) 1 h before injection of 8-OH-DPAT. The effect on search strategy, but not on locomotor activity, was less in animals with low corticosterone levels. The results suggest that hippocampal 5-HT1A receptor-mediated responses in vivo are attenuated during predominant activation of the mineralocorticoid receptor and increased after additional transient activation of the glucocorticoid receptor.