Neuropsychiatric manifestations in Parkinson’s Disease

Background:
Parkinson’s disease (PD) is characterized by the progressive degeneration of dopamine (DA) neurons in the substantia nigra (SN) and the development of Lewy bodies within affected dopaminergic cells in the SN, cerebral cortex, and brainstem. PD occurs in about 1% of older adults over age 55 years (Cowen, 2012) and the age of onset is typically between 55-75 years (Jankovic, 2008). The etiology is thought to be idiopathic, although “sporadic PD” is a term used to describe PD associated with genetic polymorphisms and autosomal inheritance. It is also worth noting that an adverse reaction of antipsychotic medications include extrapyramidal side effects, which mimic parkinsonian symptoms secondary to the blockade of DA neurons.

The cardinal clinical features of PD are the movement symptoms. This is due to impaired SN projections to the striatum of the basal ganglia, which is the pathway responsible for voluntary movement. These symptoms can be categorized under the acronym “TRAP,” which include Tremors at rest, Rigidity, Akinesia (bradykinesia), and Postural instability (Jankovic, 2008). Other clinical features are secondary motor symptoms, (i.e. shuffling gait, dystonia, and dysphagia) and non-motor symptoms (i.e. autonomic dysfunction, neurobehavioral and sensory abnormalities, and pain). These symptoms manifest when “50-70% of nigrostriatal DA neurons have been lost,” (Lesage, 2009), indicating a significant period of pre-symptomatic PD between onset and the physical appearance of symptoms. However, no definitive diagnostics tests are available to test for PD before noticeable impairment.

One common early feature of PD that can predate noticeable motor symptoms by at least 4 years is olfactory deficits (Ross, 2008). The pathogenesis is unknown, but thought to be due to Lewy body formation in the olfactory structures, as well as impaired olfactory neurogenesis. Precursor olfactory cells originate in the subventricular zone between the striatum and lateral ventricle and are downregulated by the nigrostriatal lesions of PD. REM sleep behavior disorder also precedes motor symptoms and is considered a “risk factor for the development of PD” (Jankovic, 2008). It occurs in 1/3 of PD patients and is characterized by violent dream content and “potentially injurious motor activity, such as kicking and punching (Jankovic, 2008). Studies have linked the sleep abnormalities observed in PD to a 50% loss of orexin neurons, which also occurs in narcolepsy (Thannickal, 2007).

Contributing risk factors for idiopathic PD include age, environmental toxins, and oxidative stress that cause genetic mutations. Exogenous toxins was first linked to PD in the early 1980s, when substance abusers using a synthetic narcotic succumbed to a disabling parkinsinism due to the dangerous compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). This discovery led to the experimental use of MPTP in animal models to produce nigrostriatal degeneration and has since enhanced our understanding the gene-toxin interactions in PD. The effects of MPTP are age-dependent, which suggests the incidence of PD may increases over time due to synergistic effects of toxins (Di Monte, 2002). Further research shows that toxins such as specific pesticides and bacteriotoxins cause an inflammatory response that may be involved in the progression of PD. More specifically, one study found that rats exposed to lipopolysaccharide, a bacteriotoxin, in utero, had increased concentrations of cytokine tumor necrosis factor alpha, a pro-inflammatory marker, and decreased DA concentrations in the striatum secondary to a 25% decrease in tyrosine, the precursor of DA (Di Monte, 2003). Another study showed that mice exposed to herbicides had an upregulation of the protein alpha-synuclein, a component of Lewy bodies (Di Monte, 2003). These studies illustrate the effects of exogenous factors on pathology.

Neuropsychiatric Discussion:
PD is also marked by neuropsychiatric sequela that include cognitive impairment, depression, psychosis, and impulse control disorders.

Patients diagnosed with PD are twice as likely to develop mild cognitive impairment (MCI) and between 20-57% of people with PD experience MCI symptoms in the first 5 years of diagnosis (Kehagia, 2010). Moreover, studies show that the severity of the deficits may predict the progression of cognitive dysfunction and dementia in people with PD (Kehagia, 2010). Cognitive impairments early in PD include symptoms of dysexecutive syndrome, which involves difficulties with the executive functioning tasks of planning, working memory, organization, and behavioral regulation (Kehagia, 2010). These cognitive symptoms are associated with pathological changes in the fronto-striatal and mesocortical dopaminergic pathways. This latter pathway connects to the prefrontal cortex and is involved in attention and cognition (Higgins, 2013). Dementia in PD is diagnosed if the dementia begins “more than 12 months after the onset of Parkinsonism” (Cowen, 2012) and occurs in up to 40% of people with PD (Cowen, 2012). As PD is considered to be “part of the spectrum of Lewy body disease” (Cowen, 2012), dementia in PD is similar to Lewy Body dementia in that alpha-synuclein proteins found in the nigral, limbic, brainstem, and neocortical regions may lead to a fluctuating course of dementia with recurrent perceptual disturbances and hallucinations (Cowen, 2012).

Depression symptoms are common in early and advanced PD and appear in 30-40% of the PD population. The diagnosis of co-morbid depression is complicated due to overlapping symptoms with PD, such as loss of energy, reduced memory, psychomotor retardation, and altered sleep (Arsland, 2009). It is understood that the pathogenesis of depression in PD is due to decreased norepinephrine and DA release from brain stem regions that innervate limbic circuits involved in emotional processing. Depression has also been linked to changes in the amygdala, a key structure in emotional regulation. One postmortem study identified Lewy bodies in the amygdala of patients with PD and the authors concluded that up to 20% of PD patients may have a reduced amygdala volume (Remy, 2005).

Psychosis, particularly visual hallucinations, occurs in up to 37% of people with PD and are associated with dopamine agonist medications, older age, severity of disease, depression, cognitive impairment, dementia, and reduced visual acuity (Cowen, 2012). Often the visual hallucinations are marked by the perception of “seeing a figure in a shadow or mistaking one object or person for another” (Friedman, 2010). Pathologically, psychotic symptoms in PD appear to be due to impairments in cholinergic projections that modify sensory input to the visual cortex and the presence of Lewy bodies in the temporal lobe, which is the site of visual memory processing (Manganelli, 2009; Friedman, 2010). It has also been hypothesized that visual hallucinations can be attributed to REM phenomena and sleep disturbance in PD (Friedman, 2010).

Lastly, impulse control disorder in PD is found to be a function of an overdose of dopaminergic medications. When this occurs, patients experience a marked increase in impulsivity, characterized by behaviors such as, “cravings, binge eating, compulsive foraging, hypersexuality, pathological gambling, and compulsive shopping” (Jankovic, 2008). These behaviors are maintained by over-stimulation of the dopamine receptors concentrated in the mesolimbic regions, the structures involved in underlying motivation and reward anticipation. This adverse effect is compounded by reduced negative feedback inhibition secondary to the impairment of the prefrontal cortex-ventral striatal circuitry in PD and subsequent reduced executive functioning.

References:
Aarsland D, Marsh L, and Schrag A (2009). Neuropsychiatric symptoms in Parkinson’s disease. Movement Disorders, 24, 2175-86.

Cowen, P., Harrison, P., Burns, T. (2012). Shorter Oxford Textbook of Psychiatry. Oxford: Oxford University Press.

Di Monte DA, Lavasani M, Manning-Bog AB (2002). Environmental factors in Parkinson’s disease. Neurotoxicology, 23: 487–502

Di Monte DA (2003). The environment and Parkinson’s disease: is the nigrostriatal system preferentially targeted by neurotoxins? Lancet Neurology, 2, 531-8.

Friedman JH (2010) Parkinson’s disease psychosis 2010: a review article. Parkinsonism and Related Disorders, 16, 553-60.

Jankovic, J. (2008). Parkinson’s disease: clinical features and diagnosis. Journal of Neurology, Neurosurgery, and Psychiatry, 79, 368-76.

Higgins, E.S., George, M.S. (2013). The Neuroscience of Clinical Psychiatry: The Pathophysiology of Behavior and Mental Illness. Philadelphia: Lippincott Williams & Wilkins.

Kehagia AA, Barker RA, and Robbins TW (2010). Neuropsychological and clinical heterogeneity of cognitive impairment and dementia in patients with Parkinson’s disease. Lancet Neurology, 9, 1200-13.

Lesage, S., & Brice, A. (2009). Parkinson’s disease: From monogenic forms to genetic susceptibility factors. Human Molecular Genetics, 18, R48-R59.

Manganelli F, Vitale C, Santangelo G, Pisciotta C, Iodice R, Cozzolino A, et al. Functional involvement of central cholinergic circuits and visual hallucinations in Parkinson’s disease. Brain 2009; 132:2350-5.

Remy, P., Doder, M., Lees, A., Turjanski, N., & Brooks, D. (2005). Depression in parkinson’s disease: Loss of dopamine and noradrenaline innervation in the limbic system. Brain : A Journal of Neurology, 128, 1314-1322.

Ross GW et al. (2008). Association of olfactory dysfunction with risk for future Parkinson’s disease. Annals of Neurology, 63, 167-73.

Thannickal, T. C., Lai, Y., & Siegel, J. M. (2007). Hypocretin (orexin) cell loss in parkinson’s disease. Brain, 130, 1586-1595.

Toward a Neurobiological Understanding of Antisocial and Psychopathic Personalities and the Particular Role of Empathy

A nomenclature for criminal behavior and a pervasive proclivity for such has undergone several labels over the years. Sociopath, antisocial, psychopath, etc. are just a few terms that have been used interchangeably, albeit somewhat inaccurately. Our current mindset is to identify Antisocial Personality Disorder (APD) and the psychopathic personality as distinct, yet along the same continuum, with psychopathy being on the more severe end of the spectrum. In other words, a psychopath is one with an “extreme Antisocial Personality Disorder” (Pemment, 2012, p. 1).

To review briefly, APD is a pattern of disregarding the rights of others through combinations of behaviors such as law breaking, deceitfulness, impulsivity, aggressiveness, disregard for safety, irresponsibility, and a lack of remorse often manifested as rationalizing behavior (American Psychiatric Association, 2013, p. 659). Psychopathy, on the other hand, is not a diagnosable disorder from the standpoint of the Diagnostic and Statistical Manual of Mental Disorders. Instead, it has been somewhat operationalized through the work of Robert D. Hare, Ph.D. who developed the Hare Psychopathy Checklist-Revised (PCL-R); a standardized scoring tool.

The search for an organic explanation of criminal behavior is not unique to modern times. Historical texts, beginning in the 1800s, reveal a host of past hypotheses from genetic degeneracy (Lombroso), inferior bodily constitution (Hooton), correlations between body type and temperament (Sheldon), and an extra Y chromosome (Nielsen and Henriksen), whilst other early researchers began considering the effect of brain damage/lesions (Winkler and Kove) and frontal lobe impairment (Pontius) (As cited in Yochelson & Samenow, 1976).

With several additional decades of research, our modern understanding is one of “…increasing appreciation of the role of neurobiology in individual differences in personality and their pathology in personality disorders…(Siever and Weinstein, 2009, p. 361).  Speaking more directly to the topic at hand, Glenn and Raine (2011) made the claim, “There is strong evidence suggesting that brain abnormalities, whether developmental or as a result of injury, may serve as precursors to antisocial behavior” (p. 886). This would suggest that the most current theory of personality in our modern digital world is the constellation of how each of our brain regions function in tandem, whether these brain regions are the originators of our reactions or have been acted upon and molded based on our experiences.

So is there a personality feature that delineates an individual as having an antisocial or psychopathic personality? While there is no single all-encompassing answer, one characteristic certainly stands out: empathy. It has been asserted the lack of empathy is what makes such individuals dangerous, since their reduced empathy makes it is easier for them to hurt others (Oxford University Press, 2013).

Researchers are beginning to piece together brain regions that could form “The Empathy Circuit” (Pemment, 2012, p. 1). The combination of the regions identified thus far (13 regions involving the amygdala, cingulate cortex, and aspects of the dorsal, ventral, and orbitofrontal cortexes, to name a few) are important for processing emotion, decision-making, motivation, and social behavior (Baron-Cohen, 2011 as cited in Pemment, 2012). Additionally, mirror neurons have been noted as important for functional empathy where simply observing pain or suffering in others activates that particular brain region in the observer even though they themselves are not experiencing the pain first-hand (Oxford University Press, 2013). It has been postulated those with antisocial and psychopathic personalities are somehow deficient in their mirror system (2013). Indeed, Decety et al. (2013) found when psychopathic individuals were shown visual scenarios and asked to imagine pain in others, brain regions needed for empathy such as the anterior insula, anterior midcingulate cortex, somatosensory cortex, inferior frontal gyrus, and right amygdala, showed altered activations based on the severity of psychopathy. Interestingly, the ventral striatum became activated; a brain region related to experiencing pleasure (Decety et al., 2013). In summary, the researchers not only found correlations between the fMRI data and reduced arousal and concern when another is in pain, but also that the psychopaths in the study appeared to “…find the distress of others pleasurable or positively arousing” (Decety et al., 2013, p. 9)

As a result of the impairments in empathy, among other issues, treatment for those with APD and psychopathy has proven largely unsuccessful. However, ongoing research has prevented oversimplification of characterizing APD and psychopathy as merely incapable of empathy. A recent brain imaging study provides a possible starting point for treatment in our modern day. Participants with known psychopathic personalities were shown movie clips that could elicit empathic feelings (Meffert et al., 2013).  Initially empathic brain regions were not activated (2013). However, when the participants were cued to empathize with what was occurring in the clip, these regions did indeed show activation (2013). This suggests those with psychopathy are indeed capable of experiencing empathy, but do not do so spontaneously (2013).  As such, the researchers suggested therapies may need to focus on helping this stored capacity for empathy come to light and be “more automatic” (Meffert et al., 2013, p. 2562).

It is idealistically hoped that with continued neuroscience advances, the propensity for criminality can be better understood, treated, and even prevented. Perhaps the answers can be found not only through study of the antisocial and psychopathic, but also a deeper understanding of the moral and empathic person.     

 References

American Psychiatric Association. (2013). Diagnostic and statistical manual of mental    disorders (5th ed.). Arlington, VA: American Psychiatric Publishing.

Baron-Cohen, S. (2011). The science of evil. Newe York: Basic Books.

Decety, J., Chen, C., Harenski, C. and Kiehl, K.A. (2013). An fMRI study of affective perspective taking in individuals with psychopathy: Imagining another in pain does not evoke empathy. Frontiers in Human Neuroscience, 7(489), p. 1-12.

Glenn, A.L. and Raine, A. (2011). Antisocial personality disorders. In J. Decety & J. Cacioppo (Eds.) The Oxford Handbook of Social Neuroscience (pp. 885-894). New York: Oxford University Press.

Meffert, H., Gazzola, V., den Boer, J.A., Bartels, A.A., Keysers, C. (2013). Reduced    spontaneous but relatively normal deliberate vicarious representations in psychopathy. Brain, 136, 2550-2562.

Oxford University Press (2013). Brain research shows psychopathic criminals do not lack empathy, but fail to use it automatically. ScienceDaily. Retrieved from                www.sciencedaily.com/releases/2013/07/130724200412.htm.

 Pemment, J. (2012). The neurobiology of antisocial personality disorder: The quest for  rehabilitation and treatment. Aggression and Violent Behavior. http://dx.doi.org/10.1016/j.avb.2012.10.004.

Siever, L.J. and Weinstein, L.N. (2009). The neurobiology of personality disorders: Implications for psychoanalysis. Journal of The American Psychoanalytic Association, 57(2), 361-398.

Yochelson, S. and Samenow, S.E. (1976). The criminal personality volume I: A profile for change. Lanham, MD: Rowman & Littlefield Publishers, Inc.

Pica: An Untold Story

Disordered eating is defined as consumption behaviors that distress an individual or can cause serious physical or psychological harm (American Psychiatric Association, 2013).  The American Psychiatric Association recognizes a variety of eating disorders, each with their own diagnostic criteria and information (American Psychiatric Association, 2013).  The general public, and psych students in particular, are aware of the more familiar forms of disordered eating including binging, purging and restrictive eating.  Diagnoses of Anorexia Nervosa or Bulimia are unfortunately common and identified often in the media.  It is important to recognize that although these disorders are commonly thought of when discussing eating disorders, they are not the only disorders that exist.  Another disorder is actually much more prevalent than one might originally think.  Although one might be familiar with Pica, I think it is important to discuss and understand the neurobiology and information available on this debilitating disorder.

According to the DSM 5, Pica is the “eating of nonnutritive, nonfood substances over a period of at least 1 month” (American Psychiatric Association, 2013).  This eating occurs at a developmentally inappropriate age, meaning it is not the result of an infant’s nondiscriminatory eating or chewing patterns while teething (Ellis & Schnoes, 2005).  Below are some of the most common nonfood items ingested by individuals suffering with pica.

Table 1. Substances Described as Objects of Pica.

Nonfood

Ashes
Metal
Balloons
Newsprint
Burnt matches
Paint chips
Chalk
Paper
Cigarette butts
Plant leaves
Clay
Pencil erasers
Cloth
Plastic
Crayons
Powder, baby
Detergent
Powder puffs
Dirt
Sand
Feces
Soap
Fuzz
Starch
Grass
String, thread
Ice from freezer, ice cubes
Toilet tissue
Insects
Twigs
Lavatory fresheners

Image from (Rose, Porcerelli, & Neale, 2000)

Some food items may also be included on this list as they are foods not normally consumed and ingested, including chewing gum and coffee grounds (Rose et al., 2000).  Pica is most frequently seen in children over the age of two years old, but some individuals suffer throughout adulthood.  It is also important to remember that in some cultures, pica is a common practice and not indicative of psychopathology (Ellis & Schnoes, 2005).

Interestingly, pica is the eating disorder most commonly identified and diagnosed in individuals with developmental delays (Ellis & Schnoes, 2005).  Pica is especially problematic among this population because it can lead to an increased risk for serious medical side effects.  Some individuals with severe developmental delays may be at risk of not being able to effectively communicate these concerns to providers in order to seek the best care available and can therefore go untreated.  Research shows that the severity of pica in those with intellectual delays is directly correlated with the severity of an individual’s intellectual disability (Ellis & Schnoes, 2005).  Although all individuals should be thoroughly screened for the disorder, certain individuals at high risk should be properly identified using extra care and screening techniques (Ellis & Schnoes, 2005).

Individuals with intellectual disorders are not the only individuals with increased risk for the diagnosis.  Pica has been associated with other mental health disorders including depression and anxiety (Stiegler, 2005).  The relationship between pica and obsessive compulsive disorder has also been studied at great length.  The urge to eat nonnutritive substances and the subsequent compulsion to actually eat and potentially self-soothe is somewhat common (Hergüner, Özyildirim & Tanidir, 2008).  As with many OCD symptoms, pica can be a repetitive action, can cause intrusive thoughts to the patient and can results in impaired daily functioning (Hergüner, Özyildirim & Tanidir, 2008).  Prolonged pica can results in severe poisoning or exposure to environmental toxins (Ellis & Schnoes, 2005).  Medical issues including gastrointestinal distress and bowel obstruction can lead to severe complications (Ellis & Schnoes, 2005).  Anemia and zinc deficiencies are also particularly common (Stiegler, 2005).

Neurobiologically, no identifiable cause of pica has been discovered (Ellis & Schnoes, 2005).  Many theories still exist to explain the etiology of the disorder.  Several explanations are based in physiological research.  First, stress has been shown to be associated with pica.  Of course this association is not causal, but it may be that stress increases pica behaviors or may contribute to the onset of the disorder.  Child abuse, parental neglect and insufficient bonding of a parent to a child are each sources of intense stress that have been correlated with pica (Ellis & Schnoes, 2005).  Higgins and George identify food as a source of comfort for stressed patients.  They suggest that over-stimulation in the hypothalamic-pituitary-adrenal (HPA) axis in times of stress may be correlated or predictive of a decreased ability to resist pleasurable foods, or in this case, nonfood items (Higgins & George, 2013).   Although further research is needed, another theory on the emergence of pica relates to the dopaminergic system.  Research shows that decreased dopaminergic activity is associated with pica and iron deficiency.  Therefore, it may be that decreased dopamine transmission may be responsible for the evolution or maintenance of the pica disorder (Ellis & Schnoes, 2005).  Another theory identifies pica to be the result of learned behaviors by individuals who feel positively reinforced by these eating behaviors (Ellis & Schnoes, 2005).

Currently, the treatment for pica is more behavioral and psychological than pharmacological.  Some medications associated with OCD treatment are being tested for pica, but limited research has been done with little efficacy (Hergüner, Özyildirim & Tanidir, 2008).  Most evidence suggests a multidisciplinary treatment approach with the pediatrician (in the case of a child), a social worker/case manager, a psychologist or psychiatrist and the patient/family is most beneficial.  Medical treatment including the correction of any nutritional deficiencies as a result of pica should be included in the plan of care (Ellis & Schnoes, 2005).  Further research is necessary, not only to discover the etiological and neurobiological properties of pica, but also to identify improved treatments, identification techniques and patient education procedures.

References

American Psychiatric Association. (2013). Dsm 5 American Psychiatric Association.

Ellis, C.R., Schnoes, C.J. (2005). Eating disorder: Pica. Retrieved April 1, 2014, from www.emedicine.com/ped/topic1798.htm

Hergüner, Sabri; Özyildirim Ilker; Tanidir, Cansaran. (2008). Is pica an eating disorder or an obsessive–compulsive spectrum disorder? Progress in Neuro-Psychopharmacology & Biological Psychiatry, 32, 2010-2011.

Higgins, E. S., & George, M. S. (2013). Neuroscience of clinical psychiatry: The pathophysiology of behavior and mental illness Lippincott Williams & Wilkins.

Rose, E. A., Porcerelli, J. H., & Neale, A. V. (2000). Pica: Common but commonly missed. The Journal of the American Board of Family Practice, 13, 353-358.

Stiegler, L. N. (2005). Understanding pica behavior: A review for clinical and education professionals. Focus on Autism and Other Developmental Disabilities, 20, 27-38.