Deep-brain stimulation of the human nucleus accumbens-medial septum enhances memory formation.

Deep-brain stimulation (DBS) is a potential novel treatment for memory dysfunction. Current attempts to enhance memory focus on stimulating human hippocampus or entorhinal cortex. However, an alternative strategy is to stimulate brain areas providing modulatory inputs to medial temporal memory-related structures, such as the nucleus accumbens (NAc), which is implicated in enhancing episodic memory encoding. Here, we show that NAc-DBS improves episodic and spatial memory in psychiatric patients. During stimulation, NAc-DBS increased the probability that infrequent (oddball) pictures would be subsequently recollected, relative to periods off stimulation. In a second experiment, NAc-DBS improved performance in a virtual path-integration task. An optimal electrode localization analysis revealed a locus spanning postero-medio-dorsal NAc and medial septum predictive of memory improvement across both tasks. Patient structural connectivity analyses, as well as NAc-DBS-evoked hemodynamic responses in a rat model, converge on a central role for NAc in a hippocampal-mesolimbic circuit regulating encoding into long-term memory. Thus, short-lived, phasic NAc electrical stimulation dynamically improved memory, establishing a critical on-line role for human NAc in episodic memory and providing an empirical basis for considering NAc-DBS in patients with loss of memory function.

Deep Brain Stimulation for Obsessive-Compulsive Disorder: Optimal Stimulation Sites.

BACKGROUND: Deep brain stimulation (DBS) is a promising treatment option for treatment-refractory obsessive-compulsive disorder (OCD). Several stimulation targets have been used, mostly in and around the anterior limb of the internal capsule and ventral striatum. However, the precise target within this region remains a matter of debate. METHODS: Here, we retrospectively studied a multicenter cohort of 82 patients with OCD who underwent DBS of the ventral capsule/ventral striatum and mapped optimal stimulation sites in this region. RESULTS: DBS sweet-spot mapping performed on a discovery set of 58 patients revealed 2 optimal stimulation sites associated with improvements on the Yale-Brown Obsessive Compulsive Scale, one in the anterior limb of the internal capsule that overlapped with a previously identified OCD-DBS response tract and one in the region of the inferior thalamic peduncle and bed nucleus of the stria terminalis. Critically, the nucleus accumbens proper and anterior commissure were associated with beneficial but suboptimal clinical improvements. Moreover, overlap with the resulting sweet- and sour-spots significantly estimated variance in outcomes in an independent cohort of 22 patients from 2 additional DBS centers. Finally, beyond obsessive-compulsive symptoms, stimulation of the anterior site was associated with optimal outcomes for both depression and anxiety, while the posterior site was only associated with improvements in depression. CONCLUSIONS: Our results suggest how to refine targeting of DBS in OCD and may be helpful in guiding DBS programming in existing patients.

Extracellular matrix protein anosmin-1 overexpression alters dopaminergic phenotype in the CNS and the PNS with no pathogenic consequences in a MPTP model of Parkinson's disease.

The development and survival of dopaminergic neurons are influenced by the fibroblast growth factor (FGF) pathway. Anosmin-1 (A1) is an extracellular matrix protein that acts as a major regulator of this signaling pathway, controlling FGF diffusion, and receptor interaction and shuttling. In particular, previous work showed that A1 overexpression results in more dopaminergic neurons in the olfactory bulb. Prompted by those intriguing results, in this study, we investigated the effects of A1 overexpression on different populations of catecholaminergic neurons in the central (CNS) and the peripheral nervous systems (PNS). We found that A1 overexpression increases the number of dopaminergic substantia nigra pars compacta (SNpc) neurons and alters the striosome/matrix organization of the striatum. Interestingly, these numerical and morphological changes in the nigrostriatal pathway of A1-mice did not confer an altered susceptibility to experimental MPTP-parkinsonism with respect to wild-type controls. Moreover, the study of the effects of A1 overexpression was extended to different dopaminergic tissues associated with the PNS, detecting a significant reduction in the number of dopaminergic chemosensitive carotid body glomus cells in A1-mice. Overall, our work shows that A1 regulates the development and survival of dopaminergic neurons in different nuclei of the mammalian nervous system.

Directional DBS of the Fornix in Alzheimer's Disease Achieves Long-Term Benefits: A Case Report.

Background: Current treatments for Alzheimer's disease (AD) modulate global neurotransmission but are neither specific nor anatomically directed. Tailored stimulation of target nuclei will increase treatment efficacy while reducing side effects. We report the results of the first directional deep brain stimulation (dDBS) surgery and treatment of a patient with AD in an attempt to slow the progression of the disease in a woman with multi-domain, amnestic cognitive status. Methods: We aimed to assess the safety of dDBS in patients with AD using the fornix as stimulation target (primary objective) and the clinical impact of the stimulation (secondary objective). In a registered clinical trial, a female patient aged 81 years with a 2-year history of cognitive decline and diagnoses of AD underwent a bilateral dDBS surgery targeting the fornix. Stimulation parameters were set between 3.9 and 7.5 mA, 90 µs, 130 Hz for 24 months, controlling stimulation effects by 18F-fluoro-2-deoxy-D-glucose (18F-FDG) scans (baseline, 12 and 24 months), magnetoencephalography (MEG) and clinical/neuropsychological assessment (baseline, 6, 12, 18, and 24 months). Results: There were no important complications related to the procedure. In general terms, the patient showed cognitive fluctuations over the period, related to attention and executive function patterns, with no meaningful changes in any other cognitive functions, as is shown in the clinical dementia rating scale (CDR = 1) scores over the 24 months. Such stability in neuropsychological scores corresponds to the stability of the brain metabolic function, seen in PET scans. The MEG studies described low functional connectivity at baseline and a subsequent increase in the number of significant connections, mainly in the theta band, at 12 months. Conclusion: The dDBS stimulation in the fornix seems to be a safe treatment for patients in the first stage of AD. Effects on cognition seem to be mild to moderate during the first months of stimulation and return to baseline levels after 24 months, except for verbal fluency. Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/NCT03290274], identifier [NCT03290274].

Fibromyalgia Detection Based on EEG Connectivity Patterns.

OBJECTIVE: The identification of a complementary test to confirm the diagnosis of FM. The diagnosis of fibromyalgia (FM) is based on clinical features, but there is still no consensus, so patients and clinicians might benefit from such a test. Recent findings showed that pain lies in neuronal bases (pain matrices) and, in the long term, chronic pain modifies the activity and dynamics of brain structures. Our hypothesis is that patients with FM present lower levels of brain activity and therefore less connectivity than controls. METHODS: We registered the resting state EEG of 23 patients with FM and compared them with 23 control subjects' resting state recordings from the PhysioBank database. We measured frequency, amplitude, and functional connectivity, and conducted source localization (sLORETA). ROC analysis was performed on the resulting data. RESULTS: We found significant differences in brain bioelectrical activity at rest in all analyzed bands between patients and controls, except for Delta. Subsequent source analysis provided connectivity values that depicted a distinct profile, with high discriminative capacity (between 91.3-100%) between the two groups. CONCLUSIONS: Patients with FM show a distinct neurophysiological pattern that fits with the clinical features of the disease.

Are We Ready for Cell Therapy to Treat Stroke?

Clinical trials of cell therapies that target stroke started at the beginning of this century and they have experienced a significant boost in recent years as a result of promising data from basic research studies. The increase in the information available has paved the way to carry out more innovative and varied human studies. Efforts have focused on the search for a safe and effective treatment to stimulate neuro-regeneration in the brain and to reduce the sequelae of stroke in patients. Therefore, this review aims to evaluate the clinical trials using cell therapy to treat stroke published to date and assess their limitations. From 2000 to date, most of the published clinical trials have focused on phases I or II, and the vast majority of them demonstrate that stem cells are essentially safe to use when administered by different routes, with transient and mild adverse events that do not generally have severe consequences for health. In general, there is considerable variation in the trials in terms of statistical design, sample size, the cells used, the routes of administration, and the functional assessments (both at baseline and follow-up), making it difficult to compare the studies. From this general description, possibly the experimental protocol is the main element to improve in future studies. Establishing an adequate experimental and statistical design will be essential to obtain favorable and reliable results when conducting phase III clinical trials. Thus, it is necessary to standardize the criteria used in these clinical trials in order to aid comparison. Shortly, cell therapy will be a key approach in the treatment of stroke if adequate and comprehensive levels of recovery are to be achieved.

Women Neuroscientist Disciples of Pío del Río-Hortega: the Cajal School Spreads in Europe and South America.

Pio del Rio-Hortega was not only the discoverer of the microglia and oligodendroglia but also possibly the most prolific mentor of all Santiago Ramon y Cajal's disciples (Nobel awardee in Physiology or Medicine 1906 and considered as the father of modern Neuroscience). Among Río-Hortega's mentees, three exceptional women are frequently forgotten, chronologically: Pio's niece Asunción Amo del Río who worked with Río-Hortega at Madrid, Paris, and Oxford; the distinguished British neuropathologist Dorothy Russell who also worked with Don Pío at Oxford; and Amanda Pellegrino de Iraldi, the last mentee in his career. Our present work analyzes the figures of these three women who were in contact and collaborated with Don Pío del Río-Hortega, describing the influences received and the impact on their careers and the History of Neuroscience. The present work completes the contribution of women neuroscientists who worked with Cajal and his main disciples of the Spanish Neurological School both in Spain (previous work) and in other countries (present work).

Neurorestoration Approach by Biomaterials in Ischemic Stroke.

Ischemic stroke (IS) is the leading cause of disability in the western world, assuming a high socio-economic cost. One of the most used strategies in the last decade has been biomaterials, which have been initially used with a structural support function. They have been perfected, different compounds have been combined, and they have been used together with cell therapy or controlled release chemical compounds. This double function has driven them as potential candidates for the chronic treatment of IS. In fact, the most developed are in different phases of clinical trial. In this review, we will show the ischemic scenario and address the most important criteria to achieve a successful neuroreparation from the point of view of biomaterials. The spontaneous processes that are activated and how to enhance them is one of the keys that contribute to the success of the therapeutic approach. In addition, the different routes of administration and how they affect the design of biomaterials are analyzed. Future perspectives show where this broad scientific field is heading, which advances every day with the help of technology and advanced therapies.

Atomoxetine and citalopram alter brain network organization in Parkinson's disease.

Parkinson's disease has multiple detrimental effects on motor and cognitive systems in the brain. In contrast to motor deficits, cognitive impairments in Parkinson's disease are usually not ameliorated, and can even be worsened, by dopaminergic treatments. Recent evidence has shown potential benefits from restoring other neurotransmitter deficits, including noradrenergic and serotonergic transmission. Here, we study global and regional brain network organization using task-free imaging (also known as resting-state), which minimizes performance confounds and the bias towards predetermined networks. Thirty-three patients with idiopathic Parkinson's disease were studied three times in a double-blinded, placebo-controlled counter-balanced crossover design, following placebo, 40 mg oral atomoxetine (selective noradrenaline reuptake inhibitor) or 30 mg oral citalopram (selective serotonin reuptake inhibitor). Neuropsychological assessments were performed outside the scanner. Seventy-six controls were scanned without medication to provide normative data for comparison to the patient cohort. Graph theoretical analysis of task-free brain connectivity, with a random 500-node parcellation, was used to measure the effect of disease in placebo-treated state (versus unmedicated controls) and pharmacological intervention (drug versus placebo). Relative to controls, patients on placebo had executive impairments (reduced fluency and inhibitory control), which was reflected in dysfunctional network dynamics in terms of reduced clustering coefficient, hub degree and hub centrality. In patients, atomoxetine improved fluency in proportion to plasma concentration (P = 0.006, r 2 = 0.24), and improved response inhibition in proportion to increased hub Eigen centrality (P = 0.044, r 2 = 0.14). Citalopram did not improve fluency or inhibitory control, but its influence on network integration and efficiency depended on disease severity: clustering (P = 0.01, r 2 = 0.22), modularity (P = 0.043, r 2 = 0.14) and path length (P = 0.006, r 2 = 0.25) increased in patients with milder forms of Parkinson's disease, but decreased in patients with more advanced disease (Unified Parkinson's Disease Rating Scale motor subscale part III > 30). This study supports the use of task-free imaging of brain networks in translational pharmacology of neurodegenerative disorders. We propose that hub connectivity contributes to cognitive performance in Parkinson's disease, and that noradrenergic treatment strategies can partially restore the neural systems supporting executive function.

The Women Neuroscientists in the Cajal School.

At the beginning of the 20th century, in view of the growing international recognition of Santiago Ramón y Cajal, the Spanish authorities took some important steps to support Cajal's scientific work. This recognition peaked in 1906, when Camillo Golgi and Santiago Ramón y Cajal shared the Nobel Prize in Physiology or Medicine. The Spanish government provided Cajal a state-of-the-art laboratory in Madrid to allow him to continue with his research and they funded salaries to pay his first tenured collaborators, the number of which increased further after the creation of the Junta para Ampliación de Estudios (JAE). The JAE was an organism set up to help promising researchers develop their careers in different ways, thereby contributing to the development of science in Spain. Although largely forgotten or relatively unknown, there has been a recent revival in the recognition of the school that developed around Cajal, collectively referred to as the Spanish Neurological School (or colloquially, as the Cajal School or School of Madrid). Almost all Cajal's collaborators were men, although a limited number of female scientists spent part of their careers at the heart of the Cajal School. Here we discuss these women and their work in the laboratory in Madrid. We have tracked the careers of Laura Forster (from Australia/United Kingdom), Manuela Serra, María Soledad Ruiz-Capillas and María Luisa Herreros (all Spanish), through their scientific publications, both in the journal founded by Cajal and elsewhere, and from other documentary sources. To complete the picture, we also outline the careers of other secondary figures that contributed to the production and running of Cajal's laboratory in Madrid. We show here that the dawn of Spanish neuroscience included a number of contributions from female researchers who to date, have received little recognition.

Simultaneous Stimulation of the Globus Pallidus Interna and the Nucleus Basalis of Meynert in the Parkinson-Dementia Syndrome.

BACKGROUND/AIM: The prevalence of cognitive symptoms in recently diagnosed Parkinson's disease (PD) patients may be as high as 60%. We report a novel deep brain stimulation (DBS) strategy targeting both motor and cognitive symptoms. METHODS: A PD patient diagnosed with mild cognitive impairment underwent DBS surgery targeting the globus pallidus interna (GPi; to treat motor symptoms) and the nucleus basalis of Meynert (NBM; to treat cognitive symptoms) using a single electrode per hemisphere. RESULTS: Compared to baseline, 2-month follow-up after GPi stimulation was associated with motor improvements, whereas partial improvements in cognitive functions were observed 3 months after the addition of NBM stimulation to GPi stimulation. CONCLUSION: This case explores an available alternative for complete DBS treatment in PD, stimulating 2 targets at different frequencies with a single electrode lead.

Stimulation of the Tractography-Defined Subthalamic Nucleus Regions Correlates With Clinical Outcomes.

BACKGROUND: Although deep brain stimulation (DBS) of the dorsolateral subthalamic nucleus (STN) is a well-established surgical treatment for patients with Parkinson disease (PD), there is still controversy about the relationship between the functional segregation of the STN and clinical outcomes. OBJECTIVE: To correlate motor and neuropsychological (NPS) outcomes with the overlap between the volume of activated tissue (VAT) and the tractography-defined regions within the STN. METHODS: Retrospective study evaluating 13 patients with PD treated with STN-DBS. With the aid of tractography, the STN was segmented into 4 regions: smaSTN (supplementary motor area STN), m1STN (primary motor area STN), mSTN (the sum of the m1STN and the smaSTN segments), and nmSTN (non-motor STN). We computed the overlap coefficients between these STN regions and the patient-specific VAT. The VAT outside of the STN was also calculated. These coefficients were then correlated with motor (Unified Parkinson's Disease Rating Scale, UPDRS III) and NPS outcomes. RESULTS: Stimulation of the mSTN segment was significantly correlated with UPDRS III and bradykinesia improvement. Stimulation of the smaSTN segment, but not the m1STN one, had a positive correlation with bradykinesia improvement. Stimulation of the nmSTN segment was negatively correlated with the improvement in rigidity. Stimulation outside of the STN was correlated with some beneficial NPS effects. CONCLUSION: Stimulation of the tractography-defined motor STN, mainly the smaSTN segment, is positively correlated with motor outcomes, whereas stimulation of the nmSTN is correlated with poor motor outcomes. Further validation of these results might help individualize and optimize targets prior to STN-DBS.

Personalized striatal targets for deep brain stimulation in obsessive-compulsive disorder.

BACKGROUND: Psychiatric conditions currently treated with deep brain stimulation (DBS), such as obsessive-compulsive disorder (OCD), are heterogeneous diseases with different symptomatic dimensions, indicating that fixed neuroanatomical DBS targets for all OCD cases may not be efficacious. OBJECTIVE/HYPOTHESIS: We tested whether the optimal DBS target for OCD is fixed for all patients or whether it is individualized and related to each patient's symptomatic content. Further, we explored if the optimal target can be predicted by combining functional neuroimaging and structural connectivity. METHODS: In a prospective, randomized, double-blinded study in 7 OCD patients, symptomatic content was characterized pre-operatively by clinical interview and OCD symptom-provocation during functional MRI. DBS electrode implantation followed a trajectory placing 4 contacts along a striatal axis (nucleus accumbens to caudate). Patients underwent three-month stimulation periods for each contact (and sham), followed by clinical evaluation. Probabilistic tractography, applied to diffusion-weighted images acquired pre-operatively, was used to study the overlap between projections from the prefrontal areas activated during symptom provocation and the volume of activated tissue of each electrode contact. RESULTS: Six patients were classified responders, with median symptomatic reduction of 50% achieved from each patient's best contact. This was located at the caudate in 4 cases and at the accumbens in 2. Critically, the anatomical locus of the best contact (accumbens or caudate) was related to an index derived by combining functional MRI responses to prevailing symptom provocation and prefronto-cortico-striatal projections defined by probabilistic tractography. CONCLUSION: Our results therefore represent a step towards personalized, content-specific DBS targets for OCD.

Publisher Correction: Sensory attenuation in Parkinson's disease is related to disease severity and dopamine dose.

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Sensory attenuation in Parkinson's disease is related to disease severity and dopamine dose.

Abnormal initiation and control of voluntary movements are among the principal manifestations of Parkinson's disease (PD). However, the processes underlying these abnormalities and their potential remediation by dopamine treatment remain poorly understood. Normally, movements depend on the integration of sensory information with the predicted consequences of action. This integration leads to a suppression in the intensity of predicted sensations, reflected in a 'sensory attenuation'. We examined this integration process and its relation to dopamine in PD, by measuring sensory attenuation. Patients with idiopathic PD (n = 18) and population-derived controls (n = 175) matched a set of target forces applied to their left index finger by a torque motor. To match the force, participants either pressed with their right index finger ('Direct' condition) or moved a knob that controlled a motor through a linear potentiometer ('Slider' condition). We found that despite changes in sensitivity to different forces, overall sensory attenuation did not differ between medicated PD patients and controls. Importantly, the degree of attenuation was negatively related to PD motor severity but positively related to individual patient dopamine dose, as measured by levodopa dose equivalent. The results suggest that dopamine could regulate the integration of sensorimotor prediction with sensory information to facilitate the control of voluntary movements.

Atomoxetine restores the response inhibition network in Parkinson's disease.

Parkinson's disease impairs the inhibition of responses, and whilst impulsivity is mild for some patients, severe impulse control disorders affect ∼10% of cases. Based on preclinical models we proposed that noradrenergic denervation contributes to the impairment of response inhibition, via changes in the prefrontal cortex and its subcortical connections. Previous work in Parkinson's disease found that the selective noradrenaline reuptake inhibitor atomoxetine could improve response inhibition, gambling decisions and reflection impulsivity. Here we tested the hypotheses that atomoxetine can restore functional brain networks for response inhibition in Parkinson's disease, and that both structural and functional connectivity determine the behavioural effect. In a randomized, double-blind placebo-controlled crossover study, 19 patients with mild-to-moderate idiopathic Parkinson's disease underwent functional magnetic resonance imaging during a stop-signal task, while on their usual dopaminergic therapy. Patients received 40 mg atomoxetine or placebo, orally. This regimen anticipates that noradrenergic therapies for behavioural symptoms would be adjunctive to, not a replacement for, dopaminergic therapy. Twenty matched control participants provided normative data. Arterial spin labelling identified no significant changes in regional perfusion. We assessed functional interactions between key frontal and subcortical brain areas for response inhibition, by comparing 20 dynamic causal models of the response inhibition network, inverted to the functional magnetic resonance imaging data and compared using random effects model selection. We found that the normal interaction between pre-supplementary motor cortex and the inferior frontal gyrus was absent in Parkinson's disease patients on placebo (despite dopaminergic therapy), but this connection was restored by atomoxetine. The behavioural change in response inhibition (improvement indicated by reduced stop-signal reaction time) following atomoxetine correlated with structural connectivity as measured by the fractional anisotropy in the white matter underlying the inferior frontal gyrus. Using multiple regression models, we examined the factors that influenced the individual differences in the response to atomoxetine: the reduction in stop-signal reaction time correlated with structural connectivity and baseline performance, while disease severity and drug plasma level predicted the change in fronto-striatal effective connectivity following atomoxetine. These results suggest that (i) atomoxetine increases sensitivity of the inferior frontal gyrus to afferent inputs from the pre-supplementary motor cortex; (ii) atomoxetine can enhance downstream modulation of frontal-subcortical connections for response inhibition; and (iii) the behavioural consequences of treatment are dependent on fronto-striatal structural connections. The individual differences in behavioural responses to atomoxetine highlight the need for patient stratification in future clinical trials of noradrenergic therapies for Parkinson's disease.

Time on timing: Dissociating premature responding from interval sensitivity in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) can cause impulsivity with premature responses, but there are several potential mechanisms. We proposed a distinction between poor decision-making and the distortion of temporal perception. Both effects may be present and interact, but with different clinical and pharmacological correlates. OBJECTIVES: This study assessed premature responding during time perception in PD. METHODS: In this study, 18 PD patients and 19 age-matched controls completed 2 temporal discrimination tasks (bisection and trisection) and a baseline reaction-time task. Timing sensitivity and decision-making processes were quantified by response and response time. An extended version of the modified difference model was used to examine the precision of time representation and the modulation of response time by stimulus ambiguity. RESULTS: In the bisection task, patients had a lower bisection point (P < .05) and reduced timing sensitivity when compared with controls (P < .001). In the trisection task, patients showed lower sensitivity in discriminating between short and medium standards (P < .05). The impairment in timing sensitivity correlated positively with patients' levodopa dose equivalent (P < .05). Critically, patients had disproportionately faster response times when compared with controls in more ambiguous conditions, and the degree of acceleration of response time increased with disease severity (P < .05). Computational modeling indicated that patients had poorer precision in time representation and stronger modulation of response time by task ambiguity, leading to smaller scaling of the decision latency (P < .05). CONCLUSIONS: These findings suggest that timing deficits in PD cannot be solely attributed to perceptual distortions, but are also associated with impulsive decision strategies that bias patients toward premature responses. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.