Recent research on mammalian sleep has shed some light on its role in maintaining a state of health.

Sleep deprivation hampers the regeneration of neurons in the hippocampus — a part of the brain which regulates memory as well as emotional responses to external stimuli. Neuronal precursor cells in the dentate gyrus of the hippocampus divide to produce new neurons. This process is hampered by extra periods of wakefulness. Disturbance of REM sleep and fragmentation of sleep are factors that can inhibit the proliferation of neurons. The current opinion is that extended periods of wakefulness, rather than absence of sleep dependent biochemical processes, can result in impaired neuron growth.

The sleep-wake cycle is regulated by diurnal variations in the secretion of melatonin. Disruption of sleep patterns and misalignment of melatonin secretion with duration of daytime are seen in patients who display mild cognitive impairment (MCI) — a stage that precedes the development of Alzheimer’s disease (AD). Onset of secretion of melatonin is early in patients with MCI than that seen in healthy individuals.

In a study of community-dwelling adults, disruption of sleep patterns and reduction in the duration of night-time sleep was positively correlated to the burden of the beta- amyloid peptide in the brain. Deposits of beta-amyloid were imaged in these patients and sleep patterns were reported by elderly members of the community.

Recent studies indicate that sleep is a period of “housekeeping” for the brain. Clearance of toxic metabolites such as the beta-amyloid peptide is enhanced during periods of sleep. The intercellular gaps between neurons increase during periods of sleep. Increased flux of cerebrospinal fluids through these channels (recently christened the ‘glymphatic system’) facilitates clearance of metabolites and toxins, such as the beta-amyloid peptide, from neurons during sleep. This is a significant discovery that provides an explanation for the association between poor sleep and development of AD.

Disruption of sleep patterns is also a risk factor for development of FrontoTemporal Dementia (FTD). Elderly patients (age 60 and above) with a confirmed diagnosis of FTD showed disruption of sleep macrostructure at an earlier age than patients diagnosed with AD. Although the profile of primary sleep disorders in both groups was similar, video-recordings of sleep and self-reported sleep patterns by patients show that loss of good sleep is evident to a greater degree in FTD patients than in AD patients.

Acute sleep deprivation, such as that experienced by on-call doctors, can affect the autonomous regulation of cardiovascular system. It can also result in increased levels of inflammatory cytokines such as interferon-gamma. Loss of sleep is also associated with a greater risk of developing insulin resistance as well as obesity.

A small pilot study has indicated that acute sleep deprivation (24 h) can cause an increase in stress response hormones like cortisol, epinephrine and norepinephrine. Loss on concentration and poor working memory was also evident in these subjects.

Disruption of circadian rhythms, owing to working night shifts, can cause disruptions in endocrine secretion in women and lead to problems with menstruation and conception.

People who habitually sleep for 6 hours or less show poor performance in attention based tasks and novel sensory inputs. These individuals show inefficient switching from memory-based tasks to attention-based tasks that demand quick processing of novel sensory inputs. What this study indicates is that new learning abilities may be compromised in people who sleep less on a regular basis. The recovery from habitual sleep deprivation may take several weeks and efficient performance in attention-based tasks can be achieved only after long-term normalization of duration of sleep.

Taking this research together, we have learned that sleep represents a period of daily recovery and reboot from environmental and metabolic stress. Getting eight hours of restful sleep in a regular pattern seems to be crucial for regulating mammalian metabolism in toto.

References

Bonakis A, Economou NT, Paparrigopoulos T, Bonanni E, Maestri M, Carnicelli L, Di Coscio E, Ktonas P, Vagiakis E, Theodoropoulos P, & Papageorgiou SG (2014). Sleep in Frontotemporal Dementia is Equally or Possibly More Disrupted, and at an Earlier Stage, When Compared to Sleep in Alzheimer’s Disease. Journal of Alzheimer’s disease : JAD, 38 (1), 85-91 PMID: 24077430

Gamble KL, Resuehr D, & Johnson CH (2013). Shift work and circadian dysregulation of reproduction. Frontiers in endocrinology, 4 PMID: 23966978

Gumenyuk V, Roth T, Korzyukov O, Jefferson C, Bowyer S, & Drake CL (2011). Habitual short sleep impacts frontal switch mechanism in attention to novelty. Sleep, 34 (12), 1659-70 PMID: 22131603

Joo EY, Yoon CW, Koo DL, Kim D, & Hong SB (2012). Adverse effects of 24 hours of sleep deprivation on cognition and stress hormones. Journal of clinical neurology (Seoul, Korea), 8 (2), 146-50 PMID: 22787499

Mendelsohn AR, & Larrick J (2013). Sleep facilitates clearance of metabolites from the brain: Glymphatic function in aging and neurodegenerative diseases. Rejuvenation research PMID: 24199995

Morselli L, Leproult R, Balbo M, & Spiegel K (2010). Role of sleep duration in the regulation of glucose metabolism and appetite. Best practice & research. Clinical endocrinology & metabolism, 24 (5), 687-702 PMID: 21112019

Naismith SL, Hickie IB, Terpening Z, Rajaratnam SW, Hodges JR, Bolitho S, Rogers NL, & Lewis SJ (2013). Circadian Misalignment and Sleep Disruption in Mild Cognitive Impairment. Journal of Alzheimer’s disease : JAD PMID: 24100124

Tobaldini E, Cogliati C, Fiorelli EM, Nunziata V, Wu MA, Prado M, Bevilacqua M, Trabattoni D, Porta A, & Montano N (2013). One night on-call: sleep deprivation affects cardiac autonomic control and inflammation in physicians. European journal of internal medicine, 24 (7), 664-70 PMID: 23601527

Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O’Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, & Nedergaard M (2013). Sleep drives metabolite clearance from the adult brain. Science (New York, N.Y.), 342 (6156), 373-7 PMID: 24136970

Image via Phadungsak Sawasdee / Shutterstock.

Although the entire set of genes involved in schizophrenia has not been identified, genetic analyses indicate that some chromosomal regions show strong correlations with characteristic behavioral deficits seen in schizophrenic patients.

One early diagnostic test is the assessment of auditory inhibition to a repeated auditory stimulus. In people without schizophrenia, a particular sound is ‘heard’ when the stimulus is provided once and is manifested as the firing of neurons. However, if the same signal is provided repeatedly the response of the neurons is diminished thereby enabling people to ignore repetitive sounds or background noise. This loss of auditory inhibition has been recorded in adults suffering from schizophrenia. The diminished inhibitory response is gauged as the ratio of responses evoked by paired auditory stimuli (S2:S1).

Similar assessments were made by Hunter and colleagues (2011) on infants 0-6 months of age to attempt to understand the role of parental psychosis, maternal depression and smoking. Recordings of responses to paired auditory stimuli were made when the infants were in their active sleep, a state that is similar to REM sleep in adults.

These scientists found that children of psychotic parents displayed impaired auditory inhibition. The auditory response to the second stimulus resembled the response to the first one, indicating lack of inhibition. In contrast, infants of parents not suffering from psychoses demonstrated intact auditory inhibition in response to paired stimuli.

Other risk factors that produced similar results were incidence of maternal depression and smoking by mothers. All infants assessed in the study had similar gestational periods of 33-38 weeks which rules out delayed development as a cause for the evident responses. These results indicate that an early diagnosis of schizophrenia is possible in early infancy and may provide a good time window of 16-18 years to bring in therapeutic interventions.

Auditory responses are shown by neurons that express the alpha-7 acetylcholine receptor. Activation of this receptor by choline is responsible for development of cerebral inhibition to auditory stimuli. In another study, Ross and colleagues (2013) have investigated a dietary intervention to establish cerebral inhibition. Pregnant women were asked to consume a supplement of phosphatidylcholine throughout pregnancy as well as for three months post delivery.  Infants were also fed with this supplement for up to three months following birth. The supplement contained twice as much phosphatidylcholine as is present in normal diets.

Recordings of auditory responses of infants showed that supplementation with phosphatidylcholine helped to restore normal cerebral inhibition to auditory responses. These results show that early developmental interventions are possible to restore the normal physiological functions of neurons that express the alpha-7 acetylcholine receptor.

Interestingly, in placebo-treated individuals, infants with the CHRNA7 genotype (bearing the defective gene for the alpha-7 receptor) displayed diminished cerebral inhibition. However, in the supplementation group, infants with the same genotype showed normal cerebral auditory inhibition.

So, dietary supplements of phosphatidylcholine can restore the physiological defects that are evident in schizophrenic individuals, at least in neuronal systems that express the alpha-7 acetylcholine receptor. Together, these studies illustrate that it may be possible to bring in restorative measures to correct schizophrenia. However, long-term follow up studies are needed to understand whether these interventions can truly bring about permanent restoration of neurocognitive deficits in schizophrenic individuals.

References

Greenwood TA, Swerdlow NR, Gur RE, Cadenhead KS, Calkins ME, Dobie DJ, Freedman R, Green MF, Gur RC, Lazzeroni LC, Nuechterlein KH, Olincy A, Radant AD, Ray A, Schork NJ, Seidman LJ, Siever LJ, Silverman JM, Stone WS, Sugar CA, Tsuang DW, Tsuang MT, Turetsky BI, Light GA, & Braff DL (2013). Genome-wide linkage analyses of 12 endophenotypes for schizophrenia from the Consortium on the Genetics of Schizophrenia. The American journal of psychiatry, 170 (5), 521-32 PMID: 23511790

Hunter SK, Kisley MA, McCarthy L, Freedman R, & Ross RG (2011). Diminished cerebral inhibition in neonates associated with risk factors for schizophrenia: parental psychosis, maternal depression, and nicotine use. Schizophrenia bulletin, 37 (6), 1200-8 PMID: 20403924

Ross RG, Hunter SK, McCarthy L, Beuler J, Hutchison AK, Wagner BD, Leonard S, Stevens KE, & Freedman R (2013). Perinatal choline effects on neonatal pathophysiology related to later schizophrenia risk. The American journal of psychiatry, 170 (3), 290-8 PMID: 23318559

Image via UbjsP / Shutterstock.

What is RCVS?

RCVS results from sudden narrowing of cerebral arteries which results in reduced flow of blood to parts of the brain. In some cases, hemorrhage under the arachnoid membrane may also be seen. RCVS is usually diagnosed using Magnetic Resonance Imaging (MRI) and Magnetic Resonance Angiography (MRA) and by eliminating other known causes of headaches. A peculiar feature of this malady is the persistence of constrictions on brain vessels for up to three months after the headache has occurred. At times, a series of constrictions – termed as a ‘beads-on-a-string’ appearance – have been noted. However, there is very little knowledge to date about the actual physiological mechanisms of this pathology.

Women are more susceptible to RCVS than men. In a study conducted by Ducros and colleagues, 90% of the patients with a confirmed diagnosis of RCVS were women, with a mean age of 46 years.

How is RCVS different from other brain vascular diseases?

A significant difference between RCVS and strokes and transient ischemic attacks is that, unlike strokes, RCVS is not caused by atherosclerosis. However, recurrent episodes of RCVS may render patients susceptible to a stroke.

Migraine headaches are a well-known pathological condition associated with the cerebral blood vessel network. The jury is still out on whether migraines are caused by sudden expansion of blood vessels or by constrictions in blood vessels resulting in reduced cranial circulation. Cerebral arteries are joined in a loop known as the Circle of Willis. There is some evidence to show that people with an incomplete Circle of Willis are more likely to suffer from migraine headaches than those with a complete loop. An association between RCVS and the Circle of Willis has not yet been shown. A significant difference between RCVS and migraines is the absence of ‘aura’ or accessory sensorimotor symptoms during an RCVS headache episode.

How is RCVS diagnosed?

Diagnosis of RCVS is complicated owing to the fact that it is known to be associated with specific physiological states such as post-partum status. Another factor that complicates diagnosis of RCVS is the fact that symptoms presented by patients are highly variable. A sudden headache, possibly accompanied by subdural or subarachnoid hemorrhage as well as constriction of blood vessels, are the usual symptoms of RCVS. However, in one case, a patient suffered from a thunderclap headache and yet the initial cranial angiography images showed normal circulation. The patient’s health deteriorated in the subsequent period despite normal blood flow to the brain and eventually the patient suffered an ischemic stroke and went into a coma. Although the patient eventually recovered, the presentation and progression of symptoms has been quite different from those seen in other cases of RCVS.

A pediatric case of RCVS has also been documented. Administration of Eletriptan to a 12-year-old boy resulted in a sudden headache and paralysis of limbs. Magnetic resonance imaging and magnetic resonance angiography showed constricted blood vessels in a pattern consistent with RCVS.

How is RCVS treated?

Since the exact pathophysiology of RCVS has not been deciphered completely, treatment options are limited. Drugs like nimodipene and verapamil have been used to treat RCVS. Recovery from RCVS is achieved in approximately 90% of the cases. Some people may suffer permanent neurological damage from RCVS episodes and mortality has been noted in a tiny fraction of cases.

As things stand, a sudden headache may turn out to be quite a serious health emergency.

References

Bugnicourt JM, Garcia PY, Peltier J, Bonnaire B, Picard C, & Godefroy O (2009). Incomplete posterior circle of willis: a risk factor for migraine? Headache, 49 (6), 879-86 PMID: 19562826

Calabrese LH, Dodick DW, Schwedt TJ, & Singhal AB (2007). Narrative review: reversible cerebral vasoconstriction syndromes. Annals of internal medicine, 146 (1), 34-44 PMID: 17200220

Cavestro C, Richetta L, L’episcopo MR, Pedemonte E, Duca S, & Di Pietrantonj C (2011). Anatomical variants of the circle of willis and brain lesions in migraineurs. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques, 38 (3), 494-9 PMID: 21515511

Chen SP, Fuh JL, & Wang SJ (2010). Reversible cerebral vasoconstriction syndrome: an under-recognized clinical emergency. Therapeutic advances in neurological disorders, 3 (3), 161-71 PMID: 21179608

Ducros A, Fiedler U, Porcher R, Boukobza M, Stapf C, & Bousser MG (2010). Hemorrhagic manifestations of reversible cerebral vasoconstriction syndrome: frequency, features, and risk factors. Stroke; a journal of cerebral circulation, 41 (11), 2505-11 PMID: 20884871

Hauge AW, Kirchmann M, & Olesen J (2010). Trigger factors in migraine with aura. Cephalalgia : an international journal of headache, 30 (3), 346-53 PMID: 19614703

Hauge AW, Kirchmann M, & Olesen J (2011). Characterization of consistent triggers of migraine with aura. Cephalalgia : an international journal of headache, 31 (4), 416-38 PMID: 20847084

Hougaard A, Amin F, Hauge AW, Ashina M, & Olesen J (2013). Provocation of migraine with aura using natural trigger factors. Neurology, 80 (5), 428-31 PMID: 23345632

Kuo CY, Yen MF, Chen LS, Fann CY, Chiu YH, Chen HH, & Pan SL (2013). Increased risk of hemorrhagic stroke in patients with migraine: a population-based cohort study. PloS one, 8 (1) PMID: 23372843

Lemmens R, Smet S, Wilms G, Demaerel P, & Thijs V (2012). Postpartum RCVS and PRES with normal initial imaging findings. Acta neurologica Belgica, 112 (2), 189-92 PMID: 22426679

Watanabe Y, Tanaka H, Takashima R, Takano M, Kimoto K, & Hirata K (2012). [Monitoring cerebral blood volume changes during migraine attack by using near-infrared spectroscopy]. Rinsho shinkeigaku = Clinical neurology, 52 (11), 1009-11 PMID: 23196499

Yoshioka S, Takano T, Ryujin F, & Takeuchi Y (2012). A pediatric case of reversible cerebral vasoconstriction syndrome with cortical subarachnoid hemorrhage. Brain & development, 34 (9), 796-8 PMID: 22285527

Image via Dim Dimich / Shutterstock.

In a recent study, Hispanic women volunteers were subjected to functional Magnetic Resonance Imaging (fMRI) while they were shown images of food as well as non-food items. These participants were also asked to state their emotional responses to food in terms of desire to eat the food items they were shown. Responses from the fMRI images were graded as per the contrast between activation patterns seen with high calorie foods versus those for non-food items. This study, to be published in print later this year, demonstrates that images of high-calorie foods elicited a greater response in the striatum nigra region of the brain, indicating a reward response. Images of high calorie foods also increased appetite and the desire to eat sweet as well as savory foods. It follows that repeated intake of sugary foods can only increase obesity.

Interestingly, the striatal response varied proportionately with the waist circumference of the participants. The overall BMI of the volunteers had no correlation with the activation response demonstrated to calorie-rich foods.

The outcomes of this study are hampered by two facts: First, the number of volunteers is small – just thirteen. Second, the volunteers were exclusively Hispanic women. Individuals from other ethnic groups were not included.

However, this initial study does provide some important insights. It shows how a high calorie diet of fast foods can have long-term effects on body weight and obesity associated metabolic syndrome. Frequent consumption of high calorie foods can set off a perpetual cycle of cravings for similar foods which in turn increase abdominal fat deposits and girth. In this study, participants with greater waist circumference demonstrated higher activation of the reward regions when challenged with high calorie food items. High calorie foods tend to be rich in refined carbohydrates and saturated fatty acids which contribute to an increase in waist circumference, creating a vicious cycle of eating and gaining more weight.

Popular American media have occasionally showcased stories about people who weigh upwards of 500 pounds and their subsequent efforts to lose weight. It is astounding how people can actually reach gigantic proportions before they can come to a decision about tackling this health issue! This study indicates one mechanism that may lead people to gain so much excess weight before they can mentally accept the fact that they are obese and take corrective measures.  An individual is likely to spend a considerable period of time being trapped in this vicious cycle of eating the wrong foods, gaining weight and floundering in food choices again before coming to terms with obesity. This study also lends support to the hypothesis that waist circumference and waist-to-hip ratio are better indices for understanding obesity than Body Mass Index (BMI). Body Mass Index also includes weight of limbs which are primarily muscular organs with heavy bones. However, waist circumference and waist-to-hip ratios are a direct measure of abdominal and gluteal fat deposits. Recent research indicates that these metrics may also indicate a predisposition towards unhealthy food choices.

The old saying ‘you are what you eat’ is turning out to be true in so many different ways.

References

Luo S, Romero A, Adam TC, Hu HH, Monterosso J, & Page KA (2013). Abdominal fat is associated with a greater brain reward response to high-calorie food cues in hispanic women. Obesity (Silver Spring, Md.) PMID: 23408738

Image via Ryan R Fox / Shutterstock.

In a recent review, Bhat, Landa and Galloway examined evidence to show that children who are at risk for ASD had deficient motor capabilities. Movements like non-uniform gait, variable stride length when walking, and underperformance in aiming tasks are evident in children who are diagnosed with ASD. Cognitive impairment is also evident in these kids. There is evidence to show that children who do not suffer from a cognitive lag but yet underperform on tasks that require physical balance and coordination of limbs may be later diagnosed as suffering from ASD.

Impaired motor coordination may also be assessed in the early years. Retrospective analyses of home videos of kids diagnosed with ASD in later years demonstrate that delayed motor skills may be judged in the first two years of childhood. Delayed development of gross motor skills like walking at the age of 24 months or more can be a sign of ASD. Likewise, delayed development of fine motor skills in the early years can also point towards the existence of ASD.

In order to address the issue, early interventions with physical therapy have been recommended. Koenig, Buckley-Reen and Garg have assessed the impact of a early yoga training program in schoolkids with ASD. In their study, kids with ASD were trained in yoga in a classroom-based program (Get Ready To Learn Yoga or GRTL) on a daily basis for 16 weeks. A control group of kids with ASD was allowed to complete a normal school morning routine. These researchers report that that at the end of 16 weeks, children in the GRTL yoga program showed reduced maladjustive behaviors as compared to those in the control group. Behavioral patterns were assessed by teachers with the aid of the Aberrant Behavior Checklist. These results indicate that classroom based physical therapy interventions may help to reduce behavioral deficiencies in kids suffering from ASD.

In another study, exercises from a martial arts technique called Kata were taught to children aged 5 to 16 diagnosed with ASD. Thirty children with ASD were selected and divided equally into control and intervention groups. Kids in the intervention group were trained in Kata techniques for 56 sessions spanning 14 weeks. Stereotypic behavior was assessed prior to and post-intervention. The results showed that the intervention group showed a reduction in stereotypic behaviors. An interesting find from this study is that the effects of martial arts training persisted even after a hiatus of 30 days during which no practice sessions were conducted.

Individuals suffering from ASD learn better from demonstrative techniques than from conceptual or instructive learning methods. Therefore, group therapy sessions where the participants are asked to learn by observing the actions of a leader are more likely to succeed in children suffering from ASD. It may be useful to integrate group activities such as dance training, yoga, or elementary martial arts training in the curricula of early learning institutions to improve motor and behavioral functions in children with ASD.

References

Capone GT, Grados MA, Kaufmann WE, Bernad-Ripoll S, & Jewell A (2005). Down syndrome and comorbid autism-spectrum disorder: characterization using the aberrant behavior checklist. American journal of medical genetics. Part A, 134 (4), 373-80 PMID: 15759262

Koenig KP, Buckley-Reen A, & Garg S (2012). Efficacy of the Get Ready to Learn yoga program among children with autism spectrum disorders: a pretest-posttest control group design. The American journal of occupational therapy : official publication of the American Occupational Therapy Association, 66 (5), 538-46 PMID: 22917120

Bahrami F, Movahedi A, Marandi SM, & Abedi A (2012). Kata techniques training consistently decreases stereotypy in children with autism spectrum disorder. Research in developmental disabilities, 33 (4), 1183-93 PMID: 22502844

Image via Attl Tibor / Shutterstock.

Experiments conducted on rats show that intravenous injection of stem cells derived from adipose tissues as well as mesenchymal stem cells derived from bone marrow supported the recovery of brain cells after a stroke. In these experiments, rats were subjected to a stroke by blocking their middle cerebral artery permanently. Stem cells from bone marrow as well as fat cells were injected 30 minutes after induction and the health of the animals was assessed at 24 hours and 14 days after stroke. In the recovery period, animals injected with stem cells showed increased levels of vascular endothelial growth factor and synaptophysin. The injected stem cells did not migrate to the site of the lesion but presumably acted as a source of neurotrophic growth factors.

In another study, stem cells from the dental pulp of human deciduous teeth (milk teeth) were grafted in the brains of mice one day after induction of a stroke. In some animals, the culture medium in which these cells were grown was used instead of the cells. Mice treated with human dental pulp stem cells and conditioned medium from these cells showed better recovery and neurological outcome than untreated mice. Grafted stem cells as well as the conditioned medium inhibited death of neurons in the recovery period and prevented cell destruction resulting from inflammation. In these experiments, the actual integration of human dental pulp stem cells into the brain tissue occurred at very low frequency.

Both studies present important insights in the process of regeneration of brain cells followed hypoxic and ischemic stroke. Stem cells secrete a number of growth factors which help to promote generation of new neurons post a stroke. The results presented by Yamagata and colleagues where just the culture medium from dental pulp stem cells was effective in restoring brain tissue and neurological functions indicate that a suitable “growth factor cocktail” can be derived from cultures of stem cells to treat stroke. Since intravenous injection of stem cells also helps recovery from stroke, it is easy to deliver such a therapeutic intervention. A xenograft of human dental pulp stem cells was successful in helping mice recover from a stroke. It would be interesting to know whether stem cells from other animal systems have a similar beneficial effect on human neurons as well.

References

Gutierrez-Fernandez M, Rodriguez-Frutos B, Ramos-Cejudo J, Vallejo-Cremades MT, Fuentes B, Cerdan S, & Diez-Tejedor E (2013). Effects of intravenous administration of allogenic bone marrow- and adipose tissue-derived mesenchymal stem cells on functional recovery and brain repair markers in experimental ischemic stroke. Stem cell research & therapy, 4 (1) PMID: 23356495

Yamagata M, Yamamoto A, Kako E, Kaneko N, Matsubara K, Sakai K, Sawamoto K, & Ueda M (2013). Human dental pulp-derived stem cells protect against hypoxic-ischemic brain injury in neonatal mice. Stroke; a journal of cerebral circulation, 44 (2), 551-4 PMID: 23238858

Image via Paul Fleet / Shutterstock.

Pharmacological options to help recovery from stroke as well as physical brain injury are limited. Patients are often left paralyzed after a stroke. One approach, to get around the fact that only a small number of post hoc curative options are available in this area of medicine, has been to pre-condition the physiological system to withstand trauma. Several plant-derived substances as well as synthetic ones have been tried out to help the brain adjust to adverse environmental conditions (very cold and very hot) as well as to physiological insults like deprivation of oxygen. These “adaptogens” or molecules that help to adapt have been known as nootropic molecules or simply nootropics. Some nootropics like an extract from Bacopa monnieri also help to enhance memory and cognitive functions even in the absence of brain trauma.

The list of known nootropics is growing and the latest molecules to join the club are Cerebrolysin and GYKI-52466. Cerebrolysin is a mixture of neuropeptides that promotes growth of neurons, thereby diminishing the impact of environmental insults. GYKI-52466 is an anti-convulsant drug.

Exposure to very hot conditions has been shown to induce neurological and behavioral changes in experimental animal models. Rats exposed to whole body hyperthermia (4 hours at ambient temperature of 38C displayed behavioral changes and impaired motor functions. Neurotransmitters like glutamate and aspartate were elevated in these rats whereas the levels of glycine and GABA had reduced under these conditions. Anatomical studies also revealed damage to neurons as well as glial cells and a breakdown of the blood-brain barrier. Usually, the blood-brain barrier in cranial blood vessels is stringently permeable to very few substances. A breakdown in the blood-brain barrier signifies greater chances of permeation of blood borne toxins and viruses into neural tissue.

These effects of exposure of the whole body to extremely hot conditions can be reversed by administration of Cerebrolysin, if it is given within one hour of exposure. In experiments carried out by Drs. Sharma, Sharma, Mossler and Muresanu, damage to brain cells could be prevented if the animals were given Cerebrolysin 30 minutes prior to exposure to high heat or within one hour post exposure. Delayed administration of Cerebrolysin did not help recovery from brain damage resulting from these conditions.

These findings are important in light of the fact that exposure of people to such temperatures is possible. Consider the daytime temperatures in places like hot deserts where temperatures of 49 degrees Celsius (Thar Desert, India), 40C (Great Victoria Desert, Australia), 58C (Sahara Desert, Libya), 50C (Gobi Desert, Mongolia) have been recorded in summer. The Afar depression in Ethiopia, which incidentally is inhabited by humans, has daytime temperatures of 48C in summer with the highest recorded temperature being 64.4C. In steel mills, in some of the hottest sections, workers may be exposed to ambient temperature of 56C.

Nootropics like Cerebrolysin may help to recover from the damage caused by whole body hyperthermia in these situations, particularly in the manufacturing industry. People from endemic cultures of hot desert regions have presumably adapted to living under these conditions and the effects of administration of nootropics to such people is probably a whole new area of investigation. However, if occasional exposure is indicated for people who otherwise would remain in a comfortable ambiance, then treatment with cerebrolysin would perhaps help to reduce the damage caused by whole body hyperthermia.

GYKI-52466 is an antagonist of the glutamate receptor which is primarily used to treat convulsions and acts as a skeletal muscle relaxant. In a recent paper, Drs. Nayak and Kerr have described experiments conducted on rats where administration of low doses of GYKI-52466 helped to reduce the extent of brain damage resulting from an induced stroke. Loss of brain tissue was lesser in animals pre-treated with GYKI-52466 than that seen in control animals which were not given the drug. Behavioral traits were also less affected in rats treated with GYKI-52466 as compared to animals not exposed to the drug.

Research into both these nootropics is in progress and accumulation of more data is certainly warranted. However, there seems to be evidence that favors prophylactic prescription of such drugs to people who are at greater risk of suffering from hyperthermia or stroke.

References

Masliah E, & Díez-Tejedor E (2012). The pharmacology of neurotrophic treatment with Cerebrolysin: brain protection and repair to counteract pathologies of acute and chronic neurological disorders. Drugs of today (Barcelona, Spain : 1998), 48 Suppl A, 3-24 PMID: 22514792

Nayak PK, & Kerr DS (2012). Low-dose GYKI-52466: Prophylactic preconditioning confers long-term neuroprotection and functional recovery following hypoxic-ischaemic brain injury. Neuroscience PMID: 23246617

Sharma HS, Sharma A, Mössler H, & Muresanu DF (2012). Neuroprotective effects of cerebrolysin, a combination of different active fragments of neurotrophic factors and peptides on the whole body hyperthermia-induced neurotoxicity: modulatory roles of co-morbidity factors and nanoparticle intoxication. International review of neurobiology, 102, 249-76 PMID: 22748833

Image via VladisChern / Shutterstock.

Beta-amyloid peptide is produced when another protein, amyloid precursor protein (APP), is sequentially cut by enzymes beta- and gamma-secretase. Yet, recent clinical trials with molecules that can target the synthesis of amyloid plaques have not been successful. Drugs like Semagacestat and scyllo-inositol (both molecules can inhibit gama-secretase) have not been useful in reducing the loss of cognitive functions in patients. The beta-amyloid peptide forms soluble polymers in the cytoplasm before being deposited in the form of fibrils outside neurons. Tramiprosate was an experimental drug tried in clinical trials to inhibit the formation of these polymers. However, this molecule did not improve cognitive deficits in a Phase II trial with patients. New molecules that may help to stop the formation of fibrils include a couple of antibodies and another compound known as PBT2 (reviewed in Teich et. al.).

If inhibitors of plaque formation are not delivering a landslide victory against Alzheimer’s then it is likely that these structural abnormalities (amyloid plaques) are actually markers for an advanced stage of the disease and not the definitive and sole causative agents. Also, amyloid plaques have been noted in geriatric patients who did not suffer from Alzheimer’s disease.

Research into familial Alzheimer’s disease (FAD) where Alzheimer’s disease can be traced through genetic lineage says that other factors, in addition to metabolism of APP, are likely to be involved in the progression of this disease. FAD-linked genes produce proteins that help to operate and maintain lysosomes in brain cells. Lysosomes are small chambers within cells specialized in degrading proteins as well as organic materials ingested by cells. These intracellular compartments facilitate recycling of organic components within a cell. Analyses of FAD-linked genes suggest that when this mechanism of degradation is hindered, it may set off events that lead to the formation of amyloid plaques and ultimately Alzheimer’s disease. In addition to impaired protein processing events in neurons, genes involved in FAD are also involved in regulating the transmission of chemical signals received at the cell membrane, into the cytoplasm.

Struble and colleagues have proposed that reduction in brain metabolic activity precedes both the onset of dementia as well as deposition of beta-amyloid fibrils. Therefore, decline in brain metabolism is more likely to be the trigger for initiation of Alzheimer’s disease.

Evidence from research suggests that deposition of beta-amyloid plaques is likely to be a late stage event in the progression of Alzheimer’s disease and other cellular events regulated by gene products of FAD-linked genes may be involved in early stages of Alzheimer’s before cognitive impairment is evident.

Why, then, are plaques formed at all? One possibility is that toxic intracellular events that lead to processing of APP into beta-amyloid peptide as well as other lysosomal activities eventually result in death of neurons and the deposition of plaques is a commemorative event. The precursors of plaques can remain soluble in the cytoplasm in the early stages of development of the disease and they change into an insoluble form (plaque deposits) only after neurons die. They are probably traces of neurons which are killed by incipient Alzheimer’s disease. This hypothesis, if tested and found true, would also explain why drugs that stop the polymerization of beta-amyloid peptide have shown somewhat better results than those which inhibit production of the peptide itself. For now, scientific evidence suggests that the fundamental cause of Alzheimer’s may lie elsewhere and amyloid plaques are not necessarily the singular causative agents of Alzheimer’s disease.

References

Pimplikar SW, Nixon RA, Robakis NK, Shen J, & Tsai LH (2010). Amyloid-independent mechanisms in Alzheimer’s disease pathogenesis. The Journal of neuroscience : the official journal of the Society for Neuroscience, 30 (45), 14946-54 PMID: 21068297

Rabinovici GD, & Jagust WJ (2009). Amyloid imaging in aging and dementia: testing the amyloid hypothesis in vivo. Behavioural neurology, 21 (1), 117-28 PMID: 19847050

Struble RG, Ala T, Patrylo PR, Brewer GJ, & Yan XX (2010). Is brain amyloid production a cause or a result of dementia of the Alzheimer’s type? Journal of Alzheimer’s disease : JAD, 22 (2), 393-9 PMID: 20847431

Teich AF, & Arancio O (2012). Is the amyloid hypothesis of Alzheimer’s disease therapeutically relevant? The Biochemical journal, 446 (2), 165-77 PMID: 22891628

Image via Juan Gaertner / Shutterstock.

The paradox is that by the time these overt symptoms develop and a confirmed diagnosis is arrived at based on them, the patient’s motor abilities are already significantly compromised. The loss of motor control results into loss of personal independence altering the quality of life considerably. Therefore the search for early symptoms of Parkinson’s disease which precede loss of motor functions is a vital topic in current neuroscience research.

A long-term research study, known as the Honolulu-Asia Aging Study (HAAS) has helped to shed some light on the development and early signs of Parkinson’s disease. In this study, 8,006 Japanese-American men were examined periodically for 40 years. From 1991, cases of Parkinson’s disease started emerging in this group. Patients were diagnosed as Parkinson’s patients based on the independent diagnoses provided by two neurologists. Brain autopsies have also been performed on deceased patients to ascertain the formation of incidental Lewy bodies — a characteristic cellular feature of Parkinson’s disease.

The study has helped to identify some behavioral patterns in patients that precede the motor symptoms of PD. Excessive day time sleepiness and loss of the sense of smell emerged as two characteristics of patients who developed PD later in life. Constipation was also identified as a feature that indicated greater risk for development of PD in this groups of patients.

Patients who developed PD also showed slower response to a computerized reaction test. In addition to the clinical diagnosis of PD, brain autopsies from people who recorded the slowest reaction times also showed development of incidental Lewy bodies. Since tests like the reaction time to a specific cognitive challenge can be quantified, it may be possible to identify threshold levels in the reaction time to separate the high-risk and low-risk patients. However, a detailed analysis of these results with an aim to identify a quantitative threshold has not been performed in this study.

All these behavioral abnormalities were assessed 7-8 years prior to death which is a sufficient time window to provide therapeutic interventions as well. The incidence of PD in patients was significantly higher when symptoms like constipation (less than one bowel movement a day) and slow reaction time to the computerized test were present simultaneously.

Blood hemoglobin levels may also turn out to be a diagnostic sign for early identification of PD. Normally, hemoglobin levels decline with age. However, in the HAAS study, individuals who had greater than or equal to 16 mg/dl hemoglobin at age 71-75 years were more likely to develop Parkinson’s disease when assessed at age 80 years. Increased levels of iron in blood has been known to be associated with PD.

Are these symptoms definitive? These symptoms are certainly not as black and white as other diagnostic tests which measure specific levels of biochemical markers of a disease. However, these signs and symptoms are of immense predictive value given that they are evident 7-8 years prior to development of motor disabilities and clinically identifiable progression of Parkinson’s disease. Moreover the actual incidence of PD in patients from the HAAS study, which have presented these symptoms, has been confirmed by looking for Lewy bodies in brain sections which is a clear symptom of Parkinson’s disease. These researchers have concluded that presence of a combination of these symptoms — loss of sense of smell, constipation, slower reaction time, high hemoglobin levels and excessive daytime sleepiness — increases the risk for developing PD subsequently.

Even if these symptoms are only indicative and not definitive signs of PD, they can alert physicians to the possibility of incipient PD in geriatric patients and provide a time window for intervention before motor control is lost.

References

Ross GW, Abbott RD, Petrovitch H, Tanner CM, & White LR (2012). Pre-motor features of Parkinson’s disease: the Honolulu-Asia Aging Study experience. Parkinsonism & related disorders, 18 Suppl 1 PMID: 22166434

Abbott RD, Ross GW, Tanner CM, Andersen JK, Masaki KH, Rodriguez BL, White LR, & Petrovitch H (2012). Late-life hemoglobin and the incidence of Parkinson’s disease. Neurobiology of aging, 33 (5), 914-20 PMID: 20709430

Image via Andreas Matzke / Shutterstock.

Typically, it affects people between the ages of 40-75 with more men being afflicted than women. In ALS, the motor neurons lose the ability to communicate with muscle cells causing the limbs to lose motility. Gradually, muscle cells atrophy, or shrink essentially because they are not “used” or controlled by motor neurons in the brain and spine anymore. Patients are able to use their mental faculties and have sufficient control over core bodily functions but lose the ability to manipulate limbs. The disease is progressive and survival rates are approximately 50% for three years post diagnosis which decline to 20% for five years post diagnosis. A small fraction of patients, about 10%, can survive for up to ten years post initiation of ALS.

As with other neurodegenerative diseases, the exact causes of ALS are not yet known to us. It is postulated that proteins that bind to ribonucleic acid (RNA) like FUS are involved in the progression of ALS. Oxidative stress in the form of reactive oxygen species also contributes to the pathogenesis of ALS. Given that the molecular nature of the disease is not yet fully understood, therapeutic options are limited and prevention or early diagnosis are the best options for patients.

In a recent study, Crew and colleagues from the Miami University have published findings of significant diagnostic potential. The onset of ALS in patients is likely to be characterized by a preceding period of metabolic changes in motor neurons, even if obvious symptoms of ALS are absent. In order to understand these changes, these researchers used magnetic resonance spectroscopy (MRS) to estimate the ratios of metabolites like choline (Cho), N-acetylaspatrate (NAA), myo-inositol (Myo) and creatine (Cr) in the neck region of people who were mutant for an enzyme , Superoxide dismutase (SOD, and therefore more likely to suffer from neurodegenerative diseases like ALS), normal individuals and patients with a confirmed diagnosis of ALS. People with the mutant enzyme did not show symptoms of ALS at the time the study was conducted. NAA is a marker for loss of neurons. It is usually estimated as an absolute value or as a ratio of other metabolites like Cho and Cr.

Their results show that the ratios of NAA/Cr and NAA/Myo were reduced in people with the mutant enzyme to the same extent as in people with a confirmed diagnosis of ALS. In both these groups, these two ratios were reduced by ~40% when compared against similar ratios from healthy individuals. The ratio of Myo/Cr was reduced by ~10% in people with mutant SOD but not in normal individuals or in ALS patients. Likewise, the ratio of NAA/Cho was reduced by 24% in ALS patients compared against a similar ratio in healthy subjects. However, subjects with mutant SOD did not show a similar reduction in the NAA/Cho ratio.

These results show that it may be possible to understand presymptomatic stages of ALS in high risk groups with the help of a non-invasive technique like magnetic resonance spectroscopy and arrive at molecular criteria that define the onset of ALS. The technique may also be developed into a fast and non-invasive diagnostic tool.

References

Carew JD, Nair G, Pineda-Alonso N, Usher S, Hu X, & Benatar M (2011). Magnetic resonance spectroscopy of the cervical cord in amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases, 12 (3), 185-91 PMID: 21143004

Carew JD, Nair G, Andersen PM, Wuu J, Gronka S, Hu X, & Benatar M (2011). Presymptomatic spinal cord neurometabolic findings in SOD1-positive people at risk for familial ALS. Neurology, 77 (14), 1370-5 PMID: 21940617

Federico A, Cardaioli E, Da Pozzo P, Formichi P, Gallus GN, & Radi E (2012). Mitochondria, oxidative stress and neurodegeneration. Journal of the neurological sciences, 322 (1-2), 254-62 PMID: 22669122

Gitler AD (2012). TDP-43 and FUS/TLS yield a target-rich haul in ALS. Nature neuroscience, 15 (11), 1467-9 PMID: 23103989

Image via David Fowler / Shutterstock.

Exposure to cannabis at a young age has been increasing steadily in the American population. Gonzalez and Swanson have reviewed evidence from longitudinal studies on abuse of cannabis in their paper to be published soon in the Proceedings of the National Academy of Sciences (PNAS). Data they have presented shows that there is a steady increase in the number of 8th-, 10th-, and 12th-graders who experiment with marijuana since the 1991-1997. In 2011, nearly 40% of 12th graders have reported to have tried out marijuana. Long term addiction is the obvious inherent risk in ‘trying out’ marijuana. However, the timing of first exposure and persistent use can have more debilitating effects than just dependence. In a longitudinal study, called the DunedIn study, 1073 participants have been tracked from birth to mid-life. Results of this long-term study have been published online in August 2012 in a paper authored by Meier and colleagues in PNAS. The lifestyle of participants in this study was gauged through interviews conducted in the intervening years as well as from reports provided by other informants. The study subjects were asked to take tests to assess their cognitive abilities at the age of 13 and subsequently at 38 years of age. The tests showed that early-onset use as well as persistent use of cannabis resulted in decline in neurological tasks performed by people. Independent reportage by the participant’s colleagues and family members also confirmed the existence of neurological as well as psychological deficits. People in this study who had never used marijuana had increased IQ at the age of 38 as compared to their performance in these tests at the onset of adolescence. However, people who consumed cannabis regularly over the period of 20 years, showed a definite decline in their IQ levels. This specific decline in mental capabilities was not buffered by other sociological factors like education indicating that persistent cannabis use resulted in long-term physiological changes in the brain. Observations recorded by third-party informants (informants were people whom the cannabis users nominated as “people who knew the subjects well”) suggested that cannabis users had reduced attention span and memory issues.

Although this data has come from people with long-term dependence on cannabis, the age of onset of cannabis usage is also important. The decline in IQ was prominent for cannabis users who began using it during adolescence as against those whose first exposure to this intoxicant was in adulthood. Significantly, the neurological deficits in adolescence-onset cannabis users were not restored by subsequent de-addiction or reduction in frequency of cannabis use. These findings are significant in light of increasing acceptance of pot as one of the rites of passage in the growing years. Another study by Van Ryzin and colleagues suggests that quality of family life and peer influence are the major predictors of cannabis usage in kids of age 12-23 years. In their study of 998 adolescents, good familial ties and absence of cannabis abusers from the peer network were found to be instrumental in helping kids avoid exposure to cannabis as well as alcohols and other intoxicants.

In Nova Scotia, a study of 976 high school students showed that cannabis users were at greater risk for depression than people who were into substance abuse of any other sort.

Notwithstanding general public opinion, medical evidence related to the effects of marijuana on brain and cognitive functions points towards abstinence from marijuana as a recreational drug.

References

Gonzalez R, & Swanson JM (2012). Long-term effects of adolescent-onset and persistent use of cannabis. Proceedings of the National Academy of Sciences of the United States of America, 109 (40), 15970-1 PMID: 23012451

Meier MH, Caspi A, Ambler A, Harrington H, Houts R, Keefe RS, McDonald K, Ward A, Poulton R, & Moffitt TE (2012). Persistent cannabis users show neuropsychological decline from childhood to midlife. Proceedings of the National Academy of Sciences of the United States of America, 109 (40) PMID: 22927402

Rasic D, Weerasinghe S, Asbridge M, & Langille DB (2012). Longitudinal associations of cannabis and illicit drug use with depression, suicidal ideation and suicidal attempts among Nova Scotia high school students. Drug and alcohol dependence PMID: 23041136

Van Ryzin MJ, Fosco GM, & Dishion TJ (2012). Family and peer predictors of substance use from early adolescence to early adulthood: an 11-year prospective analysis. Addictive behaviors, 37 (12), 1314-24 PMID: 22958864

Image via Nikita Starichenko / Shutterstock.

Resting state fMRI images of men undergoing opioid substitution therapy showed that areas of the brain engaged in reward perception, motivation, memory and self-control show significantly different activity than comparable regions in healthy individuals. Areas like the orbitofrontal cortex, cingulate gyrus and hippocampus show consistently different resting state activities in heroin-dependent and healthy subjects. The prefrontal cortex of dependent patients was less active than that of healthy patients in the resting state, during the course of de-addiction therapy. However, this area which controls motivation as well as degree of inhibition, was observed to be highly active during periods of opioid use. Other areas of the brain like the hippocampus which regulates memory, also showed activity patterns that were different from those in healthy subjects, in the resting state in addicted individuals. These images shed light on the mechanism of addiction in people and the areas of the brain that are engaged, perhaps constitutively, in sustaining addiction.

Given that study participants were enrolled from de-addiction clinics, episodes of heroin abuse had already taken place in their life. It is unclear whether the same areas of the brain would show similar activity in naive individuals. If this possibility is validated by comparative studies, these fMRI imaging techniques may have tremendous diagnostic potential in identifying people who are at high risk for addiction. One drawback of this investigation is that only male patients were included in this study. Therefore, we do not know whether there are gender-based differences in the resting state brain activity of female opioid addicts.

The study does throw up interesting possibilities. It is possible to enroll naive subjects, possibly teenagers or pre-teens, and obtain baseline brain images before these people have tried out any addictive substance like tobacco, heroin or alcohol. Follow-up studies with the same people can indicate whether experience of addictive substances can change the baseline pattern of activity. This kind of long-term and long-range study may help to identify brain markers for specific addiction disorders. The study also indicates why counseling fails to have an impact on some patients. It is likely that profound changes in resting state brain activity resulting from addiction may override the effects of received and processed advice.

Reference

Zhang Y, Tian J, Yuan K, Liu P, Zhuo L, Qin W, Zhao L, Liu J, von Deneen KM, Klahr NJ, Gold MS, & Liu Y (2011). Distinct resting-state brain activities in heroin-dependent individuals. Brain research, 1402, 46-53 PMID: 21669407

Image via Dejan Gileski / Shutterstock.

Viral infections were thought to be the root cause of CFS, typically infection with the XMRV (Xenotropic Murine Related Retrovirus). However, this theory has been discarded owing to conclusive evidence that patient samples in this study were found to be contaminated. Also, absence of the virus in body fluids of patients with confirmed CFS has been reported.

Recent research actually indicates that CFS is a complex syndrome of the nervous as well as immune systems. Blood supply to the brain was found to be reduced in CFS patients when compared to that seen in normal people. Exposure to cadmium is a possible factor that may cause reduced blood flow to the brain seen in CFS patients. There are structural changes in the brain as well. CFS patients show reduced grey matter as well as white matter in occipital lobes. These structural deficits may result in abnormal visual processing as well as reduced eye-limb coordination.

Researchers from the Queen Elizabeth Hospital, Adelaide, have reported changes in the structure of the brain stem in CFS patients. Grey matter (cell bodies of neurons) is reduced in the brainstem of CFS patients and altered regulation of blood supply to various parts of the brain is also observed. Alterations in the functions of astrocytes are thought to cause these changes. Astrocytes are star-shaped cells in the brain which provide nutrients to neurons and also have a role to play in tissue repair following brain trauma. The study indicates defects in astrocytes as well as trauma to the brain stem can contribute to structural abnormalities in the brain that lead to the development of CFS.

Another model for understanding this complex disease suggests that a combination of immune factors such as increased levels of pro-inflammatory cytokines and changes in brain pathology may by jointly responsible for the development of CFS. This model can therefore accommodate the fact that CFS has been known to set in after patients have experienced a bout of infection from various known pathogens (apart from XMRV). This model suggests that infections could trigger a pro-inflammatory response as well as deplete antioxidants from the body. These changes may contribute to development of CFS.

Therapeutic approaches to CFS are limited. Supplementation with magnesium and zinc has been suggested if cadmium is detected in patients with CFS. Current therapies focus on providing relief from specific symptoms. Scientific evidence, however, indicates that an efficient therapeutic strategy can emerge only after the neuronal correlates of this disease are understood.

References

Barnden LR, Crouch B, Kwiatek R, Burnet R, Mernone A, Chryssidis S, Scroop G, & Del Fante P (2011). A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis. NMR in biomedicine, 24 (10), 1302-12 PMID: 21560176

Biswal B, Kunwar P, & Natelson BH (2011). Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling. Journal of the neurological sciences, 301 (1-2), 9-11 PMID: 21167506

Morris G, & Maes M (2012). A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome. Metabolic brain disease PMID: 22718491

Pacini S, Fiore MG, Magherini S, Morucci G, Branca JJ, Gulisano M, & Ruggiero M (2012). Could cadmium be responsible for some of the neurological signs and symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Medical hypotheses, 79 (3), 403-7 PMID: 22795611

Puri BK, Jakeman PM, Agour M, Gunatilake KD, Fernando KA, Gurusinghe AI, Treasaden IH, Waldman AD, & Gishen P (2012). Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3 T MRI study. The British journal of radiology, 85 (1015) PMID: 22128128

Image via Adam Gregor / Shutterstock.

1. Regulation of appetite and fat metabolism by leptin and adiponectin (both are hormones involved in controlling appetite) is compromised in obese individuals. In individuals of normal body weight and metabolism, leptin is released by fat cells and sends signals of satiety to the brain. In obese individuals, one would postulate that a greater number of fat cells would ensure a greater amount of leptin released to facilitate ‘early’ satiety and reduced food intake. However, leptin does not work in this fashion in obese individuals and the answer to this conundrum is found in work conducted by researchers from University of Minnesota, Austin. Burguera and colleagues have shown that passage of leptin across the blood-brain barrier is impaired in obese rats. This work provides a clue as to why leptin resistance sets in, in obese individuals. This work also indicates why high levels of leptin are found in circulation in obese animals as well as people.

2. Saturated fats increase the levels of leptin in circulation. In mice, feeding on a diet rich in saturated fats for a week resulted in reduced expression of neuropeptide Y (NPY) gene in the hypothalamus region of the brain. Intake of a high-saturated fat diet for seven weeks resulted in elevated leptin levels in plasma with persistent changes in the expression patterns of NPY. Increased levels of Neuropeptide Y result in increased fat storage and energy intake. Ironically, although levels of expression of NPY were lowered in mice fed on saturated fats for a long time; these mice possessed increased fat mass and higher levels of leptin. The effect of a high-saturated-fat diet in these studies was specific to the kind of fats fed to the mice and not related to the amount of energy consumed. Polyunsaturated fats did not bring about similar metabolic changes in the brain as well as in circulating leptin levels. Experiments with animals fed a low-fat diet also showed similar results if the fats included in the diet were saturated fats. These results suggest that inclusion of saturated fats from sources like dairy, red meats and palm oil can affect the leptin signaling in the brain, leading to obesity. Palm oil is used in packaged foods and snacks.

3. Insulin is present and active in the cavities present in the brain (known as ventricles). Insulin plays a role in regulating appetite when it is acts on a region of the brain known as the hypothalamus. High intake of saturated fats like palmitic acid (present in palm oil) and stearic acid (present in red meat and cocoa butter) interferes with insulin signaling in the brain. These fatty acids also accumulate in the brain and create a physiological crisis situation known as inflammation. Together, these events disrupt regulation of food intake and promote obesity.

4. Consumption of a high-fat diet rich in saturated fats also has a detrimental effect in the generation of new brain cells. A region of the hippocampus, the dentate gyrus, is engaged in producing new brain cells. This regenerative activity is essential for long-term memory as well as cognitive functions. Recent research conducted at Pusan National University, Korea, shows that consumption of a diet rich in saturated fats hampers the production of new brain cells in the dentate gyrus. Cell division in this region of the brain is promoted by a growth factor known as Brain-Derived Neutrophic Factor (BDNF). A high-saturated fat diet results in reduced levels of BDNF and therefore slows down the process of cell division. Another harmful effect of this kind of diet is also the promotion of inflammation in the hippocampus. Excessive oxidation of fatty acids is seen in the hippocampus in animals exposed to this kind of diet.

A rationale for limiting consumption of dietary sources of saturated fats seems to be emerging from these studies.

References

Burguera B, Couce ME, Curran GL, Jensen MD, Lloyd RV, Cleary MP, & Poduslo JF (2000). Obesity is associated with a decreased leptin transport across the blood-brain barrier in rats. Diabetes, 49 (7), 1219-23 PMID: 10909981

Park HR, Park M, Choi J, Park KY, Chung HY, & Lee J (2010). A high-fat diet impairs neurogenesis: involvement of lipid peroxidation and brain-derived neurotrophic factor. Neuroscience letters, 482 (3), 235-9 PMID: 20670674

Posey KA, Clegg DJ, Printz RL, Byun J, Morton GJ, Vivekanandan-Giri A, Pennathur S, Baskin DG, Heinecke JW, Woods SC, Schwartz MW, & Niswender KD (2009). Hypothalamic proinflammatory lipid accumulation, inflammation, and insulin resistance in rats fed a high-fat diet. American journal of physiology. Endocrinology and metabolism, 296 (5) PMID: 19116375

Townsend KL, Lorenzi MM, & Widmaier EP (2008). High-fat diet-induced changes in body mass and hypothalamic gene expression in wild-type and leptin-deficient mice. Endocrine, 33 (2), 176-88 PMID: 18483882

Wang H, Storlien LH, & Huang XF (2002). Effects of dietary fat types on body fatness, leptin, and ARC leptin receptor, NPY, and AgRP mRNA expression. American journal of physiology. Endocrinology and metabolism, 282 (6) PMID: 12006366

Image via Lipsky / Shutterstock.

The prefrontal cortex in teenagers is in a state of growth and development. Contrary to established notions, brain development continues well into the teenage years and changes in synapses (connections between brain cells that facilitate the transmission of chemical messengers between cells) occur well into adolescence.  Research on adolescent mice and rats shows that exposure to nicotine during this period has long-lasting effects. For starters, nicotine is known to be able to excite neurons bearing nicotinic acetylcholine receptors. In the prefrontal cortex, nicotine has been shown to induce greater expression of a specific subset of nicotinic acetylcholine receptors, by 34%.  In the normal course of development, the number of acetylcholine receptors declines in these cells. This phenomenon is specific to the period of adolescence since a similar increase in the number of receptors is not seen when the initial exposure to nicotine occurs in adulthood, in these animals. Research has also shown that exposure to nicotine in early adolescence enhances the nicotinic ‘reward’ feeling during adulthood. It is therefore surmised that early exposure to smoking is likely to set the stage for long-term addiction and perhaps it also explains why addiction to nicotine is so prevalent, worldwide.

One might argue that since the teenage years are a short period in the life-span of a person, occasional exposure to nicotine is not likely to leave lasting damage. Here’s the catch. Exposure to nicotine also changes the pattern of synaptic connectivity between neurons in the prefrontal cortex.  The ability of neurons to establish new synaptic connections and develop new firing patterns in response to different stimuli is also known as “synaptic plasticity”. Neuroscientists have shown that all “learning” as well as  information analysis and assimilation in the brain is a net result of the pattern of exchange of neurotransmitter molecules (also referred to as pattern of ‘firing’) between neurons which respond to training stimuli. So, the more you learn, the better you get at learning by stimulating your neurons to make new synaptic connections. However, exposure to nicotine in early adolescence, changes the pattern of firing of neurons in the prefrontal cortex. Now this change reduces the capability of neurons in the prefrontal cortex to make new synaptic connections. Therefore exposure to psychedelic and addictive substances like nicotine results in reduced synaptic plasticity and has a negative impact on cognitive processes in adult life.

All these significant changes take place in early adolescence and perhaps parental guidance may play a huge role in preventing nicotine addiction and associated cognitive deficits.

References

Adriani W, Macrì S, Pacifici R, & Laviola G (2002). Peculiar vulnerability to nicotine oral self-administration in mice during early adolescence. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 27 (2), 212-24 PMID: 12093595

Counotte DS, Goriounova NA, Moretti M, Smoluch MT, Irth H, Clementi F, Schoffelmeer AN, Mansvelder HD, Smit AB, Gotti C, & Spijker S (2012). Adolescent nicotine exposure transiently increases high-affinity nicotinic receptors and modulates inhibitory synaptic transmission in rat medial prefrontal cortex. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 26 (5), 1810-20 PMID: 22308197

Goriounova NA, & Mansvelder HD (2012). Nicotine exposure during adolescence alters the rules for prefrontal cortical synaptic plasticity during adulthood. Frontiers in synaptic neuroscience, 4 PMID: 22876231

Goriounova NA, & Mansvelder HD (2012). Nicotine exposure during adolescence leads to short- and long-term changes in spike timing-dependent plasticity in rat prefrontal cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience, 32 (31), 10484-93 PMID: 22855798

Kawai HD, Kang HA, & Metherate R (2011). Heightened nicotinic regulation of auditory cortex during adolescence. The Journal of neuroscience : the official journal of the Society for Neuroscience, 31 (40), 14367-77 PMID: 21976522

Kota D, Robinson SE, & Imad Damaj M (2009). Enhanced nicotine reward in adulthood after exposure to nicotine during early adolescence in mice. Biochemical pharmacology, 78 (7), 873-9 PMID: 19576867

Image via william langeveld / Shutterstock.