Synaesthesia: a distinct entity that is an emergent feature of adaptive neurocognitive differences.

In this article, I argue that synaesthesia is not on a continuum with neurotypical cognition. Synaesthesia is special: its phenomenology is different; it has distinct causal mechanisms; and is likely to be associated with a distinct neurocognitive profile. However, not all synaesthetes are the same, and there are quantifiable differences between them. In particular, the number of types of synaesthesia that a person possesses is a hitherto underappreciated variable that predicts cognitive differences along a number of dimensions (mental imagery, sensory sensitivity, attention to detail). Together with enhanced memory, this may constitute a common core of abilities that may go some way to explaining why synaesthesia might have evolved. I argue that the direct benefits of synaesthesia are generally limited (i.e. the synaesthetic associations do not convey novel information about the world) but, nevertheless, synaesthesia may develop due to other adaptive functions (e.g. perceptual ability, memory) that necessitate changes to design features of the brain. The article concludes by suggesting that synaesthesia forces us to reconsider what we mean by a 'normal' mind/brain. There may be multiple 'normal' neurodevelopmental trajectories that can sculpt very different ways of experiencing the world, of which synaesthesia is but one. This article is part of a discussion meeting issue 'Bridging senses: novel insights from synaesthesia'.

Mindfulness-Based Stress Reduction for Older Adults With Stress Disorders and Neurocognitive Difficulties: A Randomized Controlled Trial.

OBJECTIVE: To determine whether neurocognitive performance and clinical outcomes can be enhanced by a mindfulness intervention in older adults with stress disorders and cognitive complaints. To explore decreased hypothalamic-pituitary-adrenal (HPA) axis activity as a possible mechanism. METHODS: 103 adults aged 65 years or older with an anxiety or depressive disorder (diagnosed according to DSM-IV criteria) and subjective neurocognitive difficulties were recruited in St. Louis, Missouri, or San Diego, California, from September 2012 through August 2013 and randomly assigned in groups of 5-8 to mindfulness-based stress reduction (MBSR) or a health education control condition matched for time, attention, and credibility. The primary outcomes were memory (assessed by immediate and delayed paragraph and list recall) and cognitive control (Delis-Kaplan Executive Function System Verbal Fluency Test and Color Word Interference Test). Other outcomes included clinical symptoms (worry, depression, anxiety, and global improvement). HPA axis activity was assessed using peak salivary cortisol. Outcomes were measured immediately post-intervention and (for clinical outcomes only) at 3- and 6-month follow up. RESULTS: On the basis of intent-to-treat principles using data from all 103 participants, the mindfulness group experienced greater improvement on a memory composite score (P = .046). Groups did not differ on change in cognitive control. Participants receiving MBSR also improved more on measures of worry (P = .042) and depression (P = .049) at posttreatment and on worry (P = .02), depression (P = .002), and anxiety (P = .002) at follow-up and were more likely to be rated as much or very much improved as rated by the Clinical Global Impressions-Improvement scale (47% vs 27%, χ² = 4.5, P = .03). Cortisol level decreased to a greater extent in the mindfulness group, but only among those participants with high baseline cortisol. CONCLUSIONS: In this population of older adults with stress disorders and neurocognitive difficulties, a mindfulness intervention improves clinical outcomes such as excessive worry and depression and may include some forms of immediate memory performance. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01693874.

Neurofeedback ineffective in paediatric brain tumour survivors: Results of a double-blind randomised placebo-controlled trial.

BACKGROUND: Many paediatric brain tumour survivors (PBTS) suffer from neurocognitive impairments. Promising effects of neurofeedback (NF) on neurocognitive functioning have been reported, however research into NF for PBTS has not been conducted. We investigated the effects of NF on neurocognitive functioning in PBTS using a double-blind randomised placebo-controlled trial with a parallel-group design (Pediatric Research on Improving Speed, Memory, and Attention; the PRISMA study). METHODS: Eligible for inclusion were PBTS with neurocognitive complaints, aged 8-18 years, >2 years post-treatment. They were recruited from five medical centres in the Netherlands. A randomisation table assigned participants to 30 sessions (two per week) of either NF or placebo feedback (PF) (ratio 1:1). Participants, parents, trainers, and researchers handling the data were blinded to group assignment. Participants were assessed pre-, post- and 6 months post-training to determine whether NF training would lead to improved functioning as compared with PF training. Primary outcome measures were attention, processing speed, memory, executive functioning, visuomotor integration, and intelligence. Linear mixed models analyses were used to test differences between NF and PF training over time. RESULTS: A total of 82 children were enrolled (mean age 13.9 years, standard deviation = 3.2, 49% males); 80 participants were randomised (NF: n = 40, PF n = 40); 71 participants completed the training (NF: n = 34, PF: n = 37); 68 participants completed training and 6 months post-training assessment (NF: n = 33, PF: n = 35). Similar improvements were found over time for the two treatment groups on the primary outcomes (all p's > 0.15). CONCLUSION: Results indicated no specific treatment-effects of NF on neurocognitive functioning of PBTS.

Social isolation stress down-regulates cortical early growth response 1 (Egr-1) expression in mice.

Social isolation stress induces behavioral disturbances such as aggression, cognitive impairments, and deficits in prepulse inhibition in mice. Social isolation mice have, therefore, been studied as an animal model of neuropsychiatric disorders such as schizophrenia. Recently, the decrease in early growth response (Egr) gene expression levels were reported in the post-mortem brains of schizophrenia patients. In this study, we investigate the effects of social isolation stress on the expression levels of Egr mRNA and protein in the frontal cortex. Social isolation stress exposure significantly down-regulated the expression of Egr-1 protein and Egr-1 gene transcript in nucleus of cortical neurons in a manner dependent on a social isolation period. This stress had no effect on the expression level of Egr-1 in the striatum or the expression levels of other Egr family members (Egr-2, -3, and -4) in the frontal cortex. These results suggest that the decrease in Egr-1 expression in the frontal cortex may be involved in social isolation stress-induced behavioral abnormalities.

Withdrawal of penicillamine from zinc sulphate-penicillamine maintenance therapy in Wilson's disease: promising, safe and cheap.

BACKGROUND: Penicillamine, once considered the cornerstone of treatment for Wilson disease (WD), is rather expensive and toxic, and often causes neurological worsening. Zinc sulphate, aiming at the treatment of free-copper toxicosis, has emerged as effective, safe and cheap alternative. AIM: To assess the effect of withdrawal of penicillamine from maintenance treatment with penicillamine and zinc sulphate. PATIENTS AND METHODS: 45 patients of WD (M:F: 28:17; age at diagnosis: 13.5+/-63 years), on both penicillamine (P) and zinc sulphate (Zn), couldn't continue penicillamine due to financial constraints. Their clinical data, disability and impairment scores (Schwab and England (S&E) score, Neurological Symptom Score (NSS), and Chu staging) and follow-up data of patients maintained only on zinc sulphate were recorded. RESULTS: Majority of patients (84.4%) had neuropsychiatric manifestations. The mean duration of treatment with penicillamine (P) and zinc sulphate (P+Zn), before stopping penicillamine, was 107.4+/-67.3 months. 40 patients improved variably, while the rest didn't. They received only zinc sulphate for 27.2+/-8.5 months (range: 12 to 34) and 44 patients (97.7%) remained status quo or improved marginally. Only one patient reported worsening in dysarthria. Their disability and impairment scores during combination (penicillamine and zinc sulphate) and Zn alone were: Chu (1.3+/-0.5 vs. 1.5+/-1.9; p=0.4), NSS (1.8+/-3.1 vs. 1.5+/-2.3; p=0.03) and S&E (96.4+/-5.6 vs. 98.6+/-3.5; p=0.03). There were no adverse effects. CONCLUSIONS: Withdrawal of penicillamine from zinc sulphate/penicillamine maintenance therapy for patients with Wilson's disease was effective, safe and economic, for almost all patients. This retrospective study reiterates that zinc sulphate may be used as a preferred mode of treatment for patients with Wilson's disease.

Acute subcortical stroke and early serotonergic modification: a IDAP study.

The intensity dependence of the auditory-evoked potentials (IDAP) is inversely related to serotonergic tone. Depression is frequently observed after stroke, associated with cognitive impairment and increased mortality. Aim of this study was to investigate the serotonergic tone in acute stroke patients by IDAP. Consecutive patients with an acute stroke admitted in our stroke unit were evaluated using clinical and instrumental examinations and compared with healthy controls. The IDAP was calculated as the linear amplitude/stimulus intensity function (ASF) slope, by measuring the peak-to-peak amplitude of Nl-P2 on four blocks of different stimulus intensities. Twenty patients were enrolled; 11 had a right brain infarction; nine had depressive symptoms (DS). The ASF slope of the auditory-evoked potentials was markedly increased in stroke patients compared with controls (P = 0.021). Stroke patients with DS had a significant steeper ASF slope than controls (P = 0.017). There was no statistical difference in ASF slope between stroke patients without DS and controls. Post-stroke depression pathophysiology is still debated. Our study suggests that in acute stroke patients with DS, there is a direct involvement of the serotonergic system, regardless the degree of disability and the site of the lesion.

Cognitive impairment and celiac disease.

OBJECTIVE: To characterize the clinical, radiological, and electrophysiological laboratory profiles and histological features of patients who developed cognitive impairment temporally associated with celiac disease. DESIGN: Case series. SETTING: Referral center. PATIENTS: Patients with the onset of progressive cognitive decline within 2 years of symptomatic onset or with a severe exacerbation of biopsy-proved adult celiac disease were identified from the Mayo Clinic medical records from January 1, 1970, to December 31, 2005. Patients were excluded if an alternate cause of their cognitive impairment was identified. RESULTS: Thirteen patients (5 women) were identified. The median age at cognitive impairment onset was 64 years (range, 45-79 years), which coincided with symptom onset or exacerbation of diarrhea, steatorrhea, and abdominal cramping in 5 patients. Amnesia, acalculia, confusion, and personality changes were the most common presenting features. The average initial Short Test of Mental Status score was 28 of a total of 38 (range, 18-34), which was in the moderately impaired range. The results of neuropsychological testing suggested a trend of a frontosubcortical pattern of impairment. Ten patients had ataxia, and 4 of them also had peripheral neuropathy. Magnetic resonance imaging of the head showed nonspecific T2 hyperintensities, and electroencephalography showed nonspecific diffuse slowing. Deficiencies in folate, vitamin B(12), vitamin E, or a combination were identified in 4 patients, yet supplementation did not improve their neurological symptoms. Three patients improved or stabilized cognitively with gluten withdrawal. A detailed histological analysis revealed nonspecific gliosis. CONCLUSIONS: A possible association exists between progressive cognitive impairment and celiac disease, given the temporal relationship and the relatively high frequency of ataxia and peripheral neuropathy, more commonly associated with celiac disease. Given the impact for potential treatment of similar cases, recognition of this possible association and additional studies are warranted.

Perinatal complications and abnormal proton metabolite concentrations in frontal cortex of adolescents seen on magnetic resonance spectroscopy.

OBJECTIVE: The relation of perinatal complications to metabolism of orbitofrontal cortex was studied in 12 normal adolescents aged 13 to 17 years. BACKGROUND: Perinatal complications are associated with both (a) behavioral signs of frontal lobe dysfunction and (b) increased risk for mood disorders and schizophrenia. Perinatal complications are not usually sufficient to produce these disorders, however, suggesting an etiologic model in which perinatal complications interact with a second, familial, liability factor. The present study tested a key prediction of this "two-factor" model, namely, that perinatal complications will be associated with physiologic signs of frontal dysfunction, even in persons who have no personal or family history of these psychiatric disorders. METHODS: Subjects were screened by structured interviews with the Kiddie Schedule for Affective Disorders and Schizophrenia and had no personal or family history of psychiatric disorder. Ratios of choline and N-acetyl aspartate to creatine in orbitofrontal cortex were measured using proton magnetic resonance spectroscopy. Perinatal complications were scored with the examiners blinded to magnetic resonance spectroscopy data, applying published scales to hospital records on subjects' gestations and births. RESULTS: Perinatal complications were significantly correlated with reduced concentrations of choline and N-acetyl aspartate. CONCLUSIONS: Our results complement earlier findings of significant relations between perinatal complications and signs of frontal lobe dysfunction, as well as elevated rates of these two types of variables in mood disorders and schizophrenia.

Defining the phenotype of schizophrenia: cognitive dysmetria and its neural mechanisms.

All research on schizophrenia depends on selecting the correct phenotype to define the sample to be studied. Definition of the phenotype is complicated by the fact that there are no objective markers for the disorder. Further, the symptoms are diverse, leading some to propose that the disorder is heterogeneous and not a single disorder or syndrome. This article explores an alternative possibility. It proposes that schizophrenia may be a single disorder linked by a common pathophysiology (a neurodevelopmental mechanism), which leads to a misconnection syndrome of neural circuitry. Evidence for disruption in a specific circuit is explored: the cortical-thalamic-cerebellar-cortical circuit (CCTCC). It is suggested that a disruption in this circuit leads to an impairment in synchrony, or the smooth coordination of mental processes. When synchrony is impaired, the patient suffers from a cognitive dysmetria, and the impairment in this basic cognitive process defines the phenotype of schizophrenia and produces its diversity of symptoms.

Magnetic resonance imaging volumetric and phosphorus 31 magnetic resonance spectroscopy measurements in schizophrenia.

The purpose of this study was to examine the relationship between phosphorus magnetic resonance spectroscopy (31P MRS) parameters and left prefrontal volumes in both patients with schizophrenia and healthy subjects. 31P MRS parameters and magnetic resonance imaging (MRI) volumetric data were collected in the left prefrontal region in 10 patients with schizophrenia and 10 healthy subjects of comparable age, handedness, sex, educational level, and parental educational level. No correlations were found between any MRS parameter and grey matter volumes in the combined subjects. Phosphomonoester (PME) and grey matter volumes, however, were both correlated negatively with age. PMEs were found to be decreased, and calculated intracellular magnesium ([Mg2+]intra) was found to be increased in the patients with schizophrenia compared with healthy subjects after adjusting for left prefrontal grey and white matter, total brain volume, and age. These findings suggest that cortical grey and white manner volumes are not directly related to PME and [Mg2+]intra abnormalities in schizophrenia patients.

Persisting childish behavior after bilateral thalamic infarcts.

We report a case with bilateral paramedian thalamic infarcts. The patient showed a dramatic personality change characterized by childish behavior and euphoria; which remained unchanged for 2 years after the onset. 'Vorbeireden' characterized by approximate answers was also observed. Anterograde amnesia had quite improved after 2 years, while retrograde amnesia for 1 year prior to the stroke onset and vertical gaze palsy remained unchanged. An MRI scan demonstrated bilateral medial thalamic and right midbrain infarcts without other lesions in the brain. A position emission tomography study showed that cerebral metabolic rate for glucose was markedly decreased in both thalami and in the cerebellum, and only slightly decreased in the parietal and occipital cortical regions. Cerebral metabolic rates of glucose in the frontal and temporal cortices were within normal range. The paramedian thalamic lesions per se may be responsible for the patient's personality change, 'Vorbeireden', and amnesia.

Pathological laughing and crying.

OBJECTIVE: To review the clinical features, neurobiological correlates and treatment of pathological laughing and crying. METHOD: Selective literature review. RESULTS: Attacks of involuntary, irresistible laughing or crying have long been recognised as sequelae of brain damage. There is controversy about the clinical features of these attacks, the stimuli that provoke them and their relation to affective disorder. The pathophysiology of pathological laughing and crying is still unclear. It can occur in the presence of focal as well as diffuse brain disease. Treatment with antidepressant medications has been found to be of benefit in patients with cerebrovascular disease and multiple sclerosis. CONCLUSIONS: Clinicians should remain vigilant for these symptoms, and offer effective treatments, such as antidepressants, where indicated. Further research is needed to delineate the underlying neurobiological correlates of pathological laughing and crying. The efficacy of both pharmacological and non-pharmacological interventions requires critical evaluation.

[Frontal lobe dysfunction and depressive state: relation to endogenous character of depression]. / Dysfonctionnement frontal et état dépressif: relation avec le caractère endogène de la dépression.

A dysfunction of dorsolateral prefrontal cortex (DLPF) in major depression is suggested by functional imagery and comparative neuropsychology. However, assessment of frontal lobe syndrome with DLPF-dependent tests led to controversial results. To clarify these findings, we administered 5 of these tests (Wisconsin Card Sorting Test, Stroop Test, Trail Making Test, Tower of Toronto, verbal fluency) to 16 major depressive subjects and their 16 controls, before and after 21 days of treatment. Furthermore, we tried to assess the prognostic value of frontal lobe dysfunction, and its relation with the endogenous or exogenous nature of the depression on the one hand, the severity of the depression on the other hand. Our results suggest that the presence of a frontal lobe syndrome (defined by impaired performances at 3 tests or more) is only noted in endogenous depression; after treatment, no impairment is detected. No correlation is found with the severity of the depression. Frontal lobe syndrome does not seem to indicate poorer prognosis for current depressive episode.

Proton magnetic resonance spectroscopy of the left medial temporal and frontal lobes in chronic schizophrenia: preliminary report.

Proton magnetic resonance spectroscopy (MRS) was performed in 30 medicated schizophrenic patients and 30 normal subjects. Two groups, each containing 15 schizophrenic patients and 15 age-and sex-matched normal subjects, received MRS examinations for different volumes of interest, either the frontal lobe or the medial temporal lobe. Schizophrenic patients showed a decrease in the ratios of N-acetylaspartate (NAA)/choline-containing compounds (Cho) and NAA/creatine-phosphocreatine (Cr). The patients also showed an increase in the ratio of Cho/Cr in the left medial temporal lobe but not in the left frontal lobe. The age at onset of illness correlated positively with the ratios of NAA/Cho and NAA/Cr in the medial temporal lobe. No significant correlation was observed between the ratios of NAA/Cho, NAA/Cr, or Cho/Cr in the left medial temporal and frontal lobes and clinical symptomatology as assessed by the Scale for the Assessment of Negative Symptoms and the Positive and Negative Syndrome Scale.

Frontal intermittent rhythmic delta activity (FIRDA) in pituitary adenoma.

We report a case of FIRDA in the EEG of a patient diagnosed as major depression with pituitary adenoma and hyponatremic encephalopathy. The pituitary adenoma appeared to be a major factor responsible for FIRDA in this case. Although other factors associated with this case, i.e., diffuse encephalopathy and administration of antipsychotic drugs, have been reported to be causative, FIRDA remained in the EEG after these other factors diminished. Although size of the pituitary adenoma that might be associated with FIRDA in the EEG recording was not identified in this study, FIRDA may be associated with a small pituitary adenoma less than 10 mm in diameter. We think a diligent search for additional pathology is recommended if FIRDA is seen in the EEG of an otherwise normal patient.

Slow-wave sleep and symptomatology in schizophrenia and related psychotic disorders.

Deficits in slow-wave sleep (SWS), or delta sleep, are frequently seen in schizophrenia, but their relationship with schizophrenic symptomatology remains unclear. We examined the association between visually scored and automated measures of SWS and positive and negative symptoms in a series of unmedicated patients with schizophrenia and related psychotic disorders. Total and average automated delta wave counts were significantly inversely associated with negative symptoms overall, and the psychomotor poverty syndrome in particular. Total delta counts were also inversely related to the disorganization syndrome. No relation was seen between reality distortion or the Brief Psychiatric Rating Scale (BPRS) positive symptoms and SWS. These findings support the view that SWS deficits may be related to negative symptoms of schizophrenia and may perhaps be mediated by impaired functioning of frontothalamic neural circuits.

[Validity of the neuroethological model of obsessive-compulsive disorder]. / Zur Gültigkeit des neuroethologischen Modells der Zwangsstörung.

In the aetiology and pathogenesis of obsessive-compulsive disorders (OCD) multiple factors play a role. Among biographic, genetic and behavioral factors, biological mechanisms seem to be of relevance. Some authors have proposed a neuroethiological model. This model implies a disconnection in neural circuits, linking prefrontal cortex, basal ganglia and thalamus. This review article addressed the question as to whether brain imaging studies support this theory. Conclusions drawn from these studies must be viewed cautiously because findings are not consistent and because of methodological limitations. The validity of a neuroethiological model in OCD seems questionable.

ECT as a therapeutic option in severe brain injury.

Electroconvulsive therapy (ECT) is a safe, highly effective, and rapidly acting treatment for certain major psychiatric illnesses, most notably severe mood disorders. Disturbances in mood and behavior as symptoms of delirium may complicate recovery from traumatic brain injury, but virtually no data exist on the role of ECT as a treatment modality in such clinical situations. We describe a patient with severe, unremitting, agitated behavior following a severe closed head injury from a motor vehicle accident. The initial Glasgow Coma Scale score was 3, with computed tomographic evidence of bilateral frontal and left thalamic contusions. After awakening from a 21-day coma, the patient failed to improve beyond a Ranchos Los Amigos level 4 recovery stage. He exhibited persistent severe agitation with vocal outbursts and failed to assist in performing activities of daily living. His difficulties proved unresponsive to combined behavioral therapy and multiple trials of various psychopharmacologic agents. As an intervention of "last resort," he then received six brief-pulse, bilateral ECT treatments that resulted in marked lessening of his agitation and improvement in his ability to express his needs and participate in his self-care. Also, following the ECT, he showed a markedly enhanced response to psychopharmacologic agents. These findings may have important clinical implications for treatment of prolonged delirium after traumatic brain injury.

Encephalitis lethargica: lessons for contemporary neuropsychiatry.

Encephalitis lethargica (von Economo's encephalitis), pandemic from 1917 to 1926, opened a window on the study of behavioral consequences of infection-induced subcortical disorder. Widely varying acute manifestations included extrapyramidal disorders, myoclonus, eye movement disorders, paralyses, delirium, mood changes, inverted diurnal rhythms, and catatonia. Major pathological changes involved the substantia nigra, globus pallidus, and hypothalamus. A symptom-free recovery period was often followed by postencephalitic disturbances, typically parkinsonism in adults and conduct disorder in children. Occurrence of depression, mania, obsessive-compulsive disorder, and hyperactivity in post-encephalitic patients anticipated current concepts of the role of the basal ganglia in mood, personality, and obsessional syndromes. Observations of deferred onset and "tardy" hyperkinesias presaged current theories of the pathophysiology of tardive dyskinesia.