Brain Sci., Volume 6, Issue 3 (September 2016) – 21 articles

During the last 25 years, more than 100,000 patients have been treated with Deep Brain Stimulation (DBS). While human clinical and animal preclinical research has shed light on the complex brain-signaling disturbances that underpin e.g., Parkinson’s disease (PD), less information is available when it comes to complex psychosocial changes following DBS interventions. In this contribution, we propose to more thoroughly investigate complex personality-related changes following deep brain stimulation through refined and reliable instruments in order to help patients and their relatives in the post-surgery phase. By pursuing this goal, we first outline the clinical importance DBS has attained followed by discussing problematic and undesired non-motor problems that accompany some DBS interventions. After providing a brief definition of complex changes, we move on by outlining the measurement problem complex changes relating to non-motor symptoms currently are associated with. The latter circumstance substantiates the need for refined instruments that are able to validly assess personality-related changes. After providing a brief paragraph with regard to conceptions of personality, we argue that the latter is significantly influenced by certain competencies which themselves currently play only a tangential role in the clinical DBS-discourse. Increasing awareness of the latter circumstance is crucial in the context of DBS because it could illuminate a link between competencies and the emergence of personality-related changes, such as new-onset impulse control disorders that have relevance for patients and their relatives. Finally, we elaborate on the field of application of instruments that are able to measure personality-related changes. Full article

New deep brain stimulation (DBS) electrode designs offer operation in voltage and current mode and capability to steer the electric field (EF). The aim of the study was to compare the EF distributions of four DBS leads at equivalent amplitudes (3 V and 3.4 mA). Finite element method (FEM) simulations (n = 38) around cylindrical contacts (leads 3389, 6148) or equivalent contact configurations (leads 6180, SureStim1) were performed using homogeneous and patient-specific (heterogeneous) brain tissue models. Steering effects of 6180 and SureStim1 were compared with symmetric stimulation fields. To make relative comparisons between simulations, an EF isolevel of 0.2 V/mm was chosen based on neuron model simulations (n = 832) applied before EF visualization and comparisons. The simulations show that the EF distribution is largely influenced by the heterogeneity of the tissue, and the operating mode. Equivalent contact configurations result in similar EF distributions. In steering configurations, larger EF volumes were achieved in current mode using equivalent amplitudes. The methodology was demonstrated in a patient-specific simulation around the zona incerta and a “virtual” ventral intermediate nucleus target. In conclusion, lead design differences are enhanced when using patient-specific tissue models and current stimulation mode. Full article

Huntington’s disease (HD) is one of the most disabling degenerative movement disorders, as it not only affects the motor system but also leads to cognitive disabilities and psychiatric symptoms. Deep brain stimulation (DBS) of the pallidum is a promising symptomatic treatment targeting the core motor symptom: chorea. This article gives an overview of preliminary evidence on pathophysiology, safety and efficacy of DBS in HD. Full article

There is a long-standing debate as to whether recollection is a continuous/graded process or a threshold/all-or-none process. In the current spatial memory functional magnetic resonance imaging (fMRI) study, we examined the hippocampal activity distributions—the magnitude of activity as a function of memory strength—to determine the nature of processing in this region. During encoding, participants viewed abstract shapes in the left or right visual field. During retrieval, old shapes were presented at fixation and participants classified each shape as previously in the “left” or “right” visual field followed by an “unsure”–“sure”–“very sure” confidence rating. The contrast of left-hits and left-misses produced two activations in the hippocampus. The hippocampal activity distributions for left shapes and right shapes were completely overlapping. Critically, the magnitude of activity associated with right-miss-very sure responses was significantly greater than zero. These results support the continuous model of recollection, which predicts overlapping activity distributions, and contradict the threshold model of recollection, which predicts a threshold above which only one distribution exists. Receiver operating characteristic analysis did not distinguish between models. The present results demonstrate that the hippocampus operates in a continuous manner during recollection and highlight the utility of analyzing activity distributions to determine the nature of neural processing. Full article

Over the last few decades, brain signals have been significantly exploited for brain-computer interface (BCI) applications. In this paper, we study the extraction of features using event-related desynchronization/synchronization techniques to improve the classification accuracy for three-class motor imagery (MI) BCI. The classification approach is based on combining the features of the phase and amplitude of the brain signals using fast Fourier transform (FFT) and autoregressive (AR) modeling of the reconstructed phase space as well as the modification of the BCI parameters (trial length, trial frequency band, classification method). We report interesting results compared with those present in the literature by utilizing sequential forward floating selection (SFFS) and a multi-class linear discriminant analysis (LDA), our findings showed superior classification results, a classification accuracy of 86.06% and 93% for two BCI competition datasets, with respect to results from previous studies. Full article

Tourette syndrome (TS) is a childhood neurobehavioural disorder, characterised by the presence of motor and vocal tics, typically starting in childhood but persisting in around 20% of patients into adulthood. In those patients who do not respond to pharmacological or behavioural therapy, deep brain stimulation (DBS) may be a suitable option for potential symptom improvement. This manuscript attempts to summarise the outcomes of DBS at different targets, explore the possible mechanisms of action of DBS in TS, as well as the potential of adaptive DBS. There will also be a focus on the future challenges faced in designing optimized trials. Full article

The efficacy of Deep Brain Stimulation (DBS) for an expanding array of neurological and psychiatric disorders demonstrates directly that DBS affects the basic electroneurophysiological mechanisms of the brain. The increasing array of active electrode configurations, stimulation currents, pulse widths, frequencies, and pulse patterns provides valuable tools to probe electroneurophysiological mechanisms. The extension of basic electroneurophysiological and anatomical concepts using sophisticated computational modeling and simulation has provided relatively straightforward explanations of all the DBS parameters except frequency. This article summarizes current thought about frequency and relevant observations. Current methodological and conceptual errors are critically examined in the hope that future work will not replicate these errors. One possible alternative theory is presented to provide a contrast to many current theories. DBS, conceptually, is a noisy discrete oscillator interacting with the basal ganglia–thalamic–cortical system of multiple re-entrant, discrete oscillators. Implications for positive and negative resonance, stochastic resonance and coherence, noisy synchronization, and holographic memory (related to movement generation) are presented. The time course of DBS neuronal responses demonstrates evolution of the DBS response consistent with the dynamics of re-entrant mechanisms. Finally, computational modeling demonstrates identical dynamics as seen by neuronal activities recorded from human and nonhuman primates, illustrating the differences of discrete from continuous harmonic oscillators and the power of conceptualizing the nervous system as composed on interacting discrete nonlinear oscillators. Full article

Over the course of the development of deep brain stimulation (DBS) into a well-established therapy for Parkinson’s disease, essential tremor, and dystonia, its utility as a potential treatment for autonomic dysfunction has emerged. Dysfunction of autonomic processes is common in neurological diseases. Depending on the specific target in the brain, DBS has been shown to raise or lower blood pressure, normalize the baroreflex, to alter the caliber of bronchioles, and eliminate hyperhidrosis, all through modulation of the sympathetic nervous system. It has also been shown to improve cortical control of the bladder, directly induce or inhibit the micturition reflex, and to improve deglutition and gastric emptying. In this review, we will attempt to summarize the relevant available studies describing these effects of DBS on autonomic function, which vary greatly in character and magnitude with respect to stimulation target. Full article

The fetal and neonatal periods are critical and sensitive periods for neurodevelopment, and involve rapid brain growth in addition to natural programmed cell death (i.e., apoptosis) and synaptic pruning. Apoptosis is an important process for neurodevelopment, preventing redundant, faulty, or unused neurons from cluttering the developing brain. However, animal studies have shown massive neuronal cell death by apoptosis can also be caused by exposure to several classes of drugs, namely gamma-aminobutyric acid (GABA) agonists and N-methyl-d-aspartate (NMDA) antagonists that are commonly used in pediatric anesthesia. This form of neurotoxic insult could cause a major disruption in brain development with the potential to permanently shape behavior and cognitive ability. Evidence does suggest that psychoactive drugs alter neurodevelopment and synaptic plasticity in the animal brain, which, in the human brain, may translate to permanent neurodevelopmental changes associated with long-term intellectual disability. This paper reviews the seminal animal research on drug-induced developmental apoptosis and the subsequent clinical studies that have been conducted thus far. In humans, there is growing evidence that suggests anesthetics have the potential to harm the developing brain, but the long-term outcome is not definitive and causality has not been determined. The consensus is that there is more work to be done using both animal models and human clinical studies. Full article

Ethanol induces neurodegeneration in the developing brain, which may partially explain the long-lasting adverse effects of prenatal ethanol exposure in fetal alcohol spectrum disorders (FASD). While animal models of FASD show that ethanol-induced neurodegeneration is associated with glial activation, the relationship between glial activation and neurodegeneration has not been clarified. This review focuses on the roles of activated microglia and astrocytes in neurodegeneration triggered by ethanol in rodents during the early postnatal period (equivalent to the third trimester of human pregnancy). Previous literature indicates that acute binge-like ethanol exposure in postnatal day 7 (P7) mice induces apoptotic neurodegeneration, transient activation of microglia resulting in phagocytosis of degenerating neurons, and a prolonged increase in glial fibrillary acidic protein-positive astrocytes. In our present study, systemic administration of a moderate dose of lipopolysaccharides, which causes glial activation, attenuates ethanol-induced neurodegeneration. These studies suggest that activation of microglia and astrocytes by acute ethanol in the neonatal brain may provide neuroprotection. However, repeated or chronic ethanol can induce significant proinflammatory glial reaction and neurotoxicity. Further studies are necessary to elucidate whether acute or sustained glial activation caused by ethanol exposure in the developing brain can affect long-lasting cellular and behavioral abnormalities observed in the adult brain. Full article

Medication-overuse headache (MOH) is a challenging neurological disease, which brings frustration for sufferers and treating physicians. The patient’s lack of adherence and limited treatment evidence are frequent. The aim of this study was to compare the outcome and treatment strategies between consecutive MOH patients with daily and near-daily headache from a tertiary center. Methods: Every consecutive patient seen between January and December 2014 with the diagnosis of MOH was included. Psychiatric comorbidities, inability to inform baseline headache frequency, current or previous two-month use of preventive medications, and refusal to sign informed consent were exclusion criteria. The patients were evaluated in thorough initial consultations and divided in two groups based on their baseline headache frequency. The diagnosis and treatment strategies were clearly explained. The filling out of a detailed headache diary was requested from all patients. Endpoints compared headache frequency and adherence after two, four, and eight months between the two study groups. Results: One-hundred sixty-eight patients (31 male, 137 female) met the inclusion criteria. Nineteen patients (11.3%) were excluded. All patients had migraine or chronic migraine as primary headaches. Eighty had daily (DH), and 69 near-daily headache (NDH), at baseline consultation. Mean baseline frequency was 24.8 headache days/month (18.9 days/month for the near-daily group), average headache history was 20.6 years and mean time with >15 headache days/month was 4.8 years. Outpatient withdrawal, starting prevention, and enforcing the correct use of rescue therapy was carried out with all patients. After two months, 88% of the DH and 71% of the NDH groups adhered to treatment (p = 0.0002). The HF decreased to 12 and 9 headache days/month, respectively in DH and NDH groups (p > 0.05, non-significant) (Intention-to-treat (ITT) 14 DH; 12 NDH; p > 0.05). After four and eight months, 86.3% and 83.7% of the DH patients, and 59.4% and 55% of the NDH patients were still under treatment (p = 0.0003 and p = 0.0001). The HF decreased, respectively, to nine and nine headache days/month in the DH patients compared to 6 and 7 headache days/month in the NDH group (p > 0.05) (ITT, 12; 12; DH; 10; 11; NDH; p > 0.05). Conclusions: Although open studies provide limited conclusions, withdrawing overused medications and starting prevention may have helped the favorable outcomes. However, daily headache patients had a significantly higher adherence and lower relapse rates than near-daily headache patients, despite a considerable reduced headache frequency in both groups. Additionally, real-world patient studies are scarce and the comparison between these two subsets of patients may be useful to guide clinicians in approaching their patients. Controlled studies are necessary to confirm these observations. Full article

Increased survival after spinal cord injury (SCI) worldwide has enhanced the need for quality data that can be compared and shared between centers, countries, as well as across research studies, to better understand how best to prevent and treat SCI. Such data should be standardized and be able to be uniformly collected at any SCI center or within any SCI study. Standardization will make it possible to collect information from larger SCI populations for multi-center research studies. With this aim, the international SCI community has obtained consensus regarding the best available data and measures for use in SCI clinical practice and research. Reporting of SCI data is likewise standardized. Data elements are continuously updated and developed using an open and transparent process. There are ongoing internal, as well as external review processes, where all interested parties are encouraged to participate. The purpose of this review paper is to provide an overview of the initiatives to standardize data including the International Spinal Cord Society’s International SCI Data Sets and the National Institutes of Health, National Institute of Neurological Disorders and Stroke Common Data Elements Project within SCI and discuss future opportunities. Full article

The amygdala plays a critical role in emotion regulation. It could prove to be an effective neuromodulation target in the treatment of psychiatric conditions characterized by failure of extinction. We aim to describe our targeting technique, and intra-operative and post-operative electrodiagnostic findings associated with the placement of deep brain stimulation (DBS) electrodes in the amygdala. We used a transfrontal approach to implant DBS electrodes in the basolateral nucleus of the amygdala (BLn) of a patient suffering from severe post-traumatic stress disorder. We used microelectrode recording (MER) and awake intra-operative neurostimulation to assist with the placement. Post-operatively, the patient underwent monthly surveillance electroencephalograms (EEG). MER predicted the trajectory of the electrode through the amygdala. The right BLn showed a higher spike frequency than the left BLn. Intra-operative neurostimulation of the BLn elicited pleasant memories. The monthly EEG showed the presence of more sleep patterns over time with DBS. BLn DBS electrodes can be placed using a transfrontal approach. MER can predict the trajectory of the electrode in the amygdala and it may reflect the BLn neuronal activity underlying post-traumatic stress disorder PTSD. The EEG findings may underscore the reduction in anxiety. Full article

This magnetoencephalography (MEG) study investigated evoked ON and OFF responses to ramped and damped sounds in normal-hearing human adults. Two pairs of stimuli that differed in spectral complexity were used in a passive listening task; each pair contained identical acoustical properties except for the intensity envelope. Behavioral duration judgment was conducted in separate sessions, which replicated the perceptual bias in favour of the ramped sounds and the effect of spectral complexity on perceived duration asymmetry. MEG results showed similar cortical sites for the ON and OFF responses. There was a dominant ON response with stronger phase-locking factor (PLF) in the alpha (8–14 Hz) and theta (4–8 Hz) bands for the damped sounds. In contrast, the OFF response for sounds with rising intensity was associated with stronger PLF in the gamma band (30–70 Hz). Exploratory correlation analysis showed that the OFF response in the left auditory cortex was a good predictor of the perceived temporal asymmetry for the spectrally simpler pair. The results indicate distinct asymmetry in ON and OFF responses and neural oscillation patterns associated with the dynamic intensity changes, which provides important preliminary data for future studies to examine how the auditory system develops such an asymmetry as a function of age and learning experience and whether the absence of asymmetry or abnormal ON and OFF responses can be taken as a biomarker for certain neurological conditions associated with auditory processing deficits. Full article

Background: Transcranial direct current stimulation (tDCS) is emerging as a promising adjuvant to enhance motor function. However, there has been increasing reservations about the reliability and variability of the neuromodulatory effects evoked by tDCS. Objective/Hypothesis: The main purpose of this study was to explore the test-retest reliability and inter-individual variability of tDCS of the lower limb M1 and the relationship between transcranial magnetic stimulation (TMS)-related measures and tDCS-induced changes. Methods: Fifteen healthy participants received anodal tDCS of the lower limb M1 either when performing a lower limb motor task or when the limb was at rest. Each condition was tested twice. tDCS induced changes in corticomotor excitability of the tibialis anterior muscle were measured using TMS. A repeated measures ANOVA was performed to examine efficacy of tDCS between the two task conditions. Intraclass correlation coefficients (ICC) and variance component analyses were performed to examine reliability and variability respectively. Results: A significant increase in in corticomotor excitability was noted for the tDCS-task condition at 140% active motor threshold (AMT) and when comparing recruitment curve slopes, but not at 120% and 130% AMT. Overall, ICC values between testing days for each stimulation condition ranged from 0.6–0.9. Higher ICCs were seen for higher TMS intensities (140% AMT) and recruitment curve slopes. Inter-individual variability contributed to 34% of the exhibited variance. Conclusions: Our data suggest that the TMS-related measure used to assess neuromodulation after tDCS has an effect on its perceived test-retest reliability and inter-individual variability. Importantly, we noticed that a high reliability and low variability does not necessarily indicate clinical efficacy of tDCS as some participants showed little to no modulation of corticomotor excitability consistently. Full article

Stress is a strong risk factor in alcoholic relapse and may exert effects that mimic aspects of chronic alcohol exposure on neurobiological systems. With the neuroimmune system becoming a prominent focus in the study of the neurobiological consequences of stress, as well as chronic alcohol exposure proving to be a valuable focus in this regard, the present study sought to compare the effects of stress and chronic ethanol exposure on induction of components of the neuroimmune system. Rats were exposed to either 1 h exposure to a mild stressor (restraint) or exposure to withdrawal from 15 days of chronic alcohol exposure (i.e., withdrawal from chronic ethanol, WCE) and assessed for neuroimmune mRNAs in brain. Restraint stress alone elevated chemokine (C–C motif) ligand 2 (CCL2), interleukin-1-beta (IL-1β), tumor necrosis factor alpha (TNFα) and toll-like receptor 4 (TLR4) mRNAs in the cerebral cortex within 4 h with a return to a control level by 24 h. These increases were not accompanied by an increase in corresponding proteins. Withdrawal from WCE also elevated cytokines, but did so to varying degrees across different cytokines and brain regions. In the cortex, stress and WCE induced CCL2, TNFα, IL-1β, and TLR4 mRNAs. In the hypothalamus, only WCE induced cytokines (CCL2 and IL-1β) while in the hippocampus, WCE strongly induced CCL2 while stress and WCE induced IL-1β. In the amygdala, only WCE induced CCL2. Finally—based on the previously demonstrated role of corticotropin-releasing factor 1 (CRF1) receptor inhibition in blocking WCE-induced cytokine mRNAs—the CRF1 receptor antagonist CP154,526 was administered to a subgroup of stressed rats and found to be inactive against induction of CCL2, TNFα, or IL-1β mRNAs. These differential results suggest that stress and WCE manifest broad neuroimmune effects in brain depending on the cytokine and brain region, and that CRF inhibition may not be a relevant mechanism in non-alcohol exposed animals. Overall, these effects are complex in terms of their neuroimmune targets and neuroanatomical specificity. Further investigation of the differential distribution of cytokine induction across neuroanatomical regions, individual cell types (e.g., neuronal phenotypes and glia), severity of chronic alcohol exposure, as well as across differing stress types may prove useful in understanding differential mechanisms of induction and for targeting select systems for pharmacotherapeutic intervention in alcoholism. Full article

Evidence from human studies indicates that maternal metabolic state and malnutrition dramatically influence the risk for developing psychiatric complications in later adulthood. In this regard, the central role of polyunsaturated fatty acids (PUFAs), and particularly n-3 PUFAs, is emerging considering that epidemiological evidences have established a negative correlation between n-3 PUFA consumption and development of mood disorders. These findings were supported by clinical studies indicating that low content of n-3 PUFAs in diet is linked to an increased susceptibility to psychiatric disorders. PUFAs regulate membrane fluidity and exert their central action by modulating synaptogenesis and neurotrophic factor expression, neurogenesis, and neurotransmission. Moreover, they are precursors of molecules implicated in modulating immune and inflammatory processes in the brain. Importantly, their tissue concentrations are closely related to diet intake, especially to maternal consumption during embryonal life, considering that their synthesis from essential precursors has been shown to be inefficient in mammals. The scope of this review is to highlight the possible mechanisms of PUFA functions in the brain during pre- and post-natal period and to evaluate their role in the pathogenesis of psychiatric diseases. Full article

Oligodendrocytes wrap neuronal axons to form myelin, an insulating sheath which is essential for nervous impulse conduction along axons. Axonal myelination is highly regulated by neuronal and astrocytic signals and the maintenance of myelin sheaths is a very complex process. Oligodendrocyte damage can cause axonal demyelination and neuronal injury, leading to neurological disorders. Demyelination in the cerebrum may produce cognitive impairment in a variety of neurological disorders, including human immunodeficiency virus type one (HIV-1)-associated neurocognitive disorders (HAND). Although the combined antiretroviral therapy has markedly reduced the incidence of HIV-1-associated dementia, a severe form of HAND, milder forms of HAND remain prevalent even when the peripheral viral load is well controlled. HAND manifests as a subcortical dementia with damage in the brain white matter (e.g., corpus callosum), which consists of myelinated axonal fibers. How HIV-1 brain infection causes myelin injury and resultant white matter damage is an interesting area of current HIV research. In this review, we tentatively address recent progress on oligodendrocyte dysregulation and HAND pathogenesis. Full article

This article discusses the special features of odor-evoked memory and the current state-of-the-art in odor-evoked memory research to show how these unique experiences may be able to influence and benefit psychological and physiological health. A review of the literature leads to the conclusion that odors that evoke positive autobiographical memories have the potential to increase positive emotions, decrease negative mood states, disrupt cravings, and reduce physiological indices of stress, including systemic markers of inflammation. Olfactory perception factors and individual difference characteristics that would need to be considered in therapeutic applications of odor-evoked-memory are also discussed. This article illustrates how through the experimentally validated mechanisms of odor-associative learning and the privileged neuroanatomical relationship that exists between olfaction and the neural substrates of emotion, odors can be harnessed to induce emotional and physiological responses that can improve human health and wellbeing. Full article

Obesity is a chronic, progressive and prevalent disorder. Morbid obesity, in particular, is associated with numerous comorbidities and early mortality. In patients with morbid obesity, pharmacological and behavioral approaches often have limited results. Bariatric surgery is quite effective but is associated with operative failures and a non-negligible incidence of side effects. In the last decades, deep brain stimulation (DBS) has been investigated as a neurosurgical modality to treat various neuropsychiatric disorders. In this article we review the rationale for selecting different brain targets, surgical results and future perspectives for the use of DBS in medically refractory obesity. Full article

The Sound of Vision project involves developing a sensory substitution device that is aimed at creating and conveying a rich auditory representation of the surrounding environment to the visually impaired. However, the feasibility of such an approach is strongly constrained by neural flexibility, possibilities of sensory substitution and adaptation to changed sensory input. We review evidence for such flexibility from various perspectives. We discuss neuroplasticity of the adult brain with an emphasis on functional changes in the visually impaired compared to sighted people. We discuss effects of adaptation on brain activity, in particular short-term and long-term effects of repeated exposure to particular stimuli. We then discuss evidence for sensory substitution such as Sound of Vision involves, while finally discussing evidence for adaptation to changes in the auditory environment. We conclude that sensory substitution enterprises such as Sound of Vision are quite feasible in light of the available evidence, which is encouraging regarding such projects. Full article