Neuroanatomical Sites Research Articles

CB1 receptor stimulation in specific brain areas differently modulate anxiety-related behaviour

There is a general consensus that the effects of cannabinoid agonists on anxiety seem to be biphasic, with low doses being anxiolytic and high doses ineffective or possibly anxiogenic. Besides the behavioural effects of cannabinoids on anxiety, very few papers have dealt with the neuroanatomical sites of these effects. We investigated the effect on rat anxiety behavior of local administration of THC in the prefrontal cortex, basolateral amygdala and ventral hippocampus, brain regions belonging to the emotional circuit and containing high levels of CB1 receptors. THC microinjected at low doses in the prefrontal cortex (10μg) and ventral hippocampus (5μg) induced in rats an anxiolytic-like response tested in the elevated plus-maze, whilst higher doses lost the anxiolytic effect and even seemed to switch into an anxiogenic profile. Low THC doses (1μg) in the basolateral amygdala produced an anxiogenic-like response whereas higher doses were ineffective. All these effects were CB1-dependent and closely linked to modulation of CREB activation. Specifically, THC anxiolytic activity in the prefrontal cortex and ventral hippocampus was paralleled by an increase in CREB activation, whilst THC anxiogenic response in the basolateral amygdala was paralleled by a decrease in CREB activation. Our results suggest that while a mild activation of CB1 receptors in the prefrontal cortex and ventral hippocampus attenuates anxiety, a slight CB1 receptor stimulation in the amygdala results in an anxiogenic-like response. The molecular underpinnings of these effects involve a direct stimulation of CB1 receptors ending in pCREB modulation and/or a possible alteration in the fine tuning of local neuromodulator release.

Nocistatin attenuated the nociceptin induced c-Fos expression in the mouse hippocampus

Nocistatin and nociceptin/orphaninFQ (N/OFQ) are the two new peptides which may have roles in nociception, memory, anxiety, and other biological functions. Nocistatin acts as a functional antagonist to N/OFQ in several functions, but their neuro-anatomical sites of interaction are unknown. We investigated the effect of combined intracerebroventricular (i.c.v.) injection of nocistatin with N/OFQ, on N/OFQ induced c-Fos expression in the mouse hippocampus, using c-Fos immunohistochemistry. We found that co-injection of nocistatin with N/OFQ significantly attenuated N/OFQ induced c-Fos expression in the hippocampus.

Effect of Gabapentin on c-Fos Expression in the CNS after Paw Surgery in Rats

Gabapentin (neurontin), a GABA analogue anticonvulsant has proven to be effective in anti-nociceptive activity as well as for the treatment of anxiety. Gabapentin (GBP) is well tolerated and shows very favorable side effects profile: The exact molecular mechanism of action of GBP to block postoperative pain and stress is not known. Therefore, to identify the functional neuroanatomical target sites of GBP in post-surgery as well as its effect on postsurgical process, we examined the effects of GBP on c-Fos expression in the supraspinal part of the central nervous system in rats. Using a well-validated rat model of surgical pain, we studied the neuroanatomical functional target sites of gabapentin after paw surgery. The effect of GBP was examined by means of c-Fos immunohistochemistry. A single intraperitoneal injection (i.p.) of GBP (150 mg/kg) or saline (control) was administered 20 min before surgical incision in the paw under anesthesia. Ninety minutes after surgical incision, the deeply anesthetized rats were perfused transcardially with 4% paraformaldehyde. Serial 40-microm-thick sections of whole brain (except spinal cord) were cut and processed by immunohistochemistry to locate and quantify the sites and number of neurons with c-Fos immunoreactivity. Detection of c-Fos protein was performed using the peroxidase-antiperoxidase detection protocol. Our present study demonstrated that compared to control, administration of GBP (150 mg/kg, i.p.) before paw surgery significantly (p < 0.01) attenuated the incision-induced c-Fos expression only in the paraventricular nucleus of the hypothalamus. In addition, GBP-induced increase in c-Fos expression was observed in the dorsal raphe (DRN) and in the nucleus raphe magnus. Present results indicate that GBP may differentially modulate c-Fos expression in surgical paw incision. Moreover, this study provides some clue to examine whether GBP exerts its action simultaneously through two separate pathways in post-surgery.

Practical Rat Neuropathology

The nervous system is composed of many anatomically and functionally interrelated parts, which tend to be sensitive to artifacts. Although specific design details for neuropathological evaluations in rats will be driven by the goals of a specific study, many features of tissue collection, processing, and examination will be common to all neuropathology evaluations. Cost-effective, high-quality evaluations can occur if rats are exsanguinated quickly, brains are removed with minimal handling to maintain structural integrity and avoid dark neurons, immersion fixed quickly and thoroughly, and trimmed and processed to consistently survey multiple areas. Most evaluations can be based on hematoxylin and eosin-stained sections; however, the availability of an epi-fluorescent microscope is useful for identification of neurodegeneration in hematoxylin and eosinstained sections, and special stains may be required to answer specific questions. The evaluation requires that both the technical staff and investigator have at least a working knowledge of a few easily identified neuroanatomic sites based on a detailed atlas. (The J Histotechnol 30:115, 2007)Submitted March 1, 2007; accepted with revisions April 11, 2007

Leptin and the Control of Food Intake: Neurons in the Nucleus of the Solitary Tract Are Activated by Both Gastric Distension and Leptin

Leptin reduces food intake by an unspecified mechanism. Studies show that forebrain ventricular leptin delivery increases the inhibitory effects of gastrointestinal (GI) stimulation on intake and amplifies the electrophysiological response to gastric distension in neurons of the medial subnucleus of the nucleus tractus solitarius (mNTS). However, forebrain ventricular delivery leaves unspecified the neuroanatomical site(s) mediating leptin's effect on intake. Detailed anatomical analysis in rats and mice by phosphorylated signal transducer and activator of transcription 3 immunohistochemistry shows that hindbrain leptin-responsive neurons are located exclusively within the mNTS. Here, we investigate 1) whether leptin and gastric distension affect the same mNTS neurons and 2) whether the intake-inhibitory action of gastric distension is potentiated by hindbrain leptin delivery. Twenty-five minutes after gastric balloon distension or sham distension, rats were injected with leptin or vehicle and killed 35 min later. Double-fluorescent immunohistochemistry for phosphorylated signal transducer and activator of transcription 3 and c-Fos revealed that about 40% of leptin-responsive cells also respond to gastric distension. A paradigm was then developed to examine the relationship between leptin and gastric distension volume on intake inhibition. At subthreshold levels, hindbrain ventricular leptin or distension volume were without effect. When combined, an interaction occurred that significantly reduced food intake. We conclude that 1) leptin-responsive neurons in the hindbrain are primarily located in the mNTS at the level of the area postrema, a key vagal afferent projection zone of the GI system; 2) a significant proportion of leptin-responsive neurons in the mNTS are activated by stomach distension; and 3) leptin delivered to the hindbrain is sufficient to potentiate the intake-suppressive effects of an otherwise ineffective volume of gastric distension. These results are consistent with the hypothesis that leptin acts directly on neurons within the mNTS to reduce food intake through an interaction with GI signal processing.

The neuropathology of acquired pre- and perinatal brain injuries

Acquired pre- and perinatal brain injuries comprise a significant proportion of perinatal neuropathology. They are associated with placental abnormalities, maternal factors, multiple gestations, and preterm labor, as well as with the later development of cerebral palsy and developmental delay. The patterns of perinatal brain injury depend on the etiology (often hypoxic-ischemic) and the timing relative to the development of the fetal nervous system, since the vulnerabilities of gray and white matter differ across postconceptional age and by neuroanatomic site. Nevertheless, characteristic features allow determination of the approximate age and cause of each pattern of injury in the perinatal brain.

Gabapentin completely attenuated the acute morphine induced c-Fos expression in the rat striatum

The neuro-anatomical sites and molecular mechanism of action of gabapentin (GBP)-morphine interaction to prevent and reverse morphine side effects as well as enhancement of the analgesic effect of morphine is not known. Therefore, we examined the combined effects of GBP-Morphine on acute morphine induced c-Fos expression in rat striatum. The combined effect of GBP-Morphine was examined by means of c-Fos immunohistochemistry. A single intraperitoneal injection (i.p.) of morphine (10 mg/kg), saline (control), co-injection of GBP (150 mg/kg) with morphine (10 mg/kg) was administered under anaesthesia. Ninety minutes after drugs administration the deeply anesthetized rats were perfused transcardially with 4% paraformaldehyde. Serial 40 mum thick sections of brain were cut and processed by immunohistochemistry to locate and quantify the sites and number of neurons with c-Fos immunoreactivity. Detection of c-Fos protein was performed using the peroxidase-antiperoxidase (PAP) detection protocol. Our present study demonstrated that, administration of GBP (150 mg/kg, i.p.) in combination with morphine (10 mg/kg, i.p.) significantly (p < 0.01) attenuated the acute morphine (10 mg/kg, i.p.) induced c-Fos expression in the rat striatum. Present results showed that GBP-morphine combination action prevented the acute morphine induced c-Fos expression in rat striatum. Moreover, this study provides first evidence of neuro-anatomical site and that GBP neutralized the morphine induced activation of rat striatum.

Anxiogenic-like effects of mCPP microinfusions into the amygdala (but not dorsal or ventral hippocampus) in mice exposed to elevated plus-maze

Serotonin (5-HT) can either increase or decrease anxiety-like behaviour in animals, actions that depend upon neuroanatomical site of action and 5-HT receptor subtype. Although systemic studies with 5-HT 2 receptor agonists and antagonists suggest a facilitatory role for this receptor subtype in anxiety, somewhat inconsistent results have been obtained when such compounds have been directly applied to limbic targets such as the hippocampus and amygdala. The present study investigated the effects of the 5-HT 2B/2C receptor agonist mCPP bilaterally microinjected into the dorsal hippocampus (DH: 0, 0.3, 1.0 or 3.0 nmol/0.2 μl), the ventral hippocampus (VH: 0, 0.3, 1.0 or 3.0 nmol/0.2 μl) or the amygdaloid complex (0, 0.15, 0.5, 1.0 or 3.0 nmol/0.1 μl) in mice exposed to the elevated plus-maze (EPM). Test sessions were videotaped and subsequently scored for conventional indices of anxiety (percentage of open arm entries and percentage of open arm time) and locomotor activity (closed arm entries). Results showed that mCPP microinfusions into the DH or VH failed to affect any behavioural measure in the EPM. However, when injected into the amygdaloid complex, the dose of 1.0 nmol of this 5HT 2B/2C receptor agonist increased behavioural indices of anxiety without significantly altering general activity levels. This anxiogenic-like effect of mCPP was selectively and completely blocked by local injection of a behaviourally-inactive dose of SDZ SER-082 (10 nmol/0.1 μl), a preferential 5-HT 2C receptor antagonist. These data suggest that 5HT 2C receptors located within the amygdaloid complex (but not the dorsal or ventral hippocampus) play a facilitatory role in plus-maze anxiety in mice.

Anxiolytic-like effect of cannabinoids injected into the rat dorsolateral periaqueductal gray

Contradictory results exist concerning the effects of systemic injections of CB 1 cannabinoid receptor agonists on anxiety-related behaviors. Direct drug administration into brain structures related to aversive responses can potentially help to clarify the role of cannabinoids on anxiety. One such structure is the midbrain dorsolateral periaqueductal gray (dlPAG). Therefore, the aim of this study was to test the hypothesis that the activation of the CB 1 receptor in the dlPAG would attenuate anxiety-related behaviors. Male Wistar rats with cannula aimed at the dlPAG received injections of the endogenous cannabinoid anandamide, the anandamide transport inhibitor AM404, the anandamide analogue ACEA or the CB 1 receptor antagonist AM251, and were submitted to the elevated plus maze (EPM), an animal model of anxiety. Anandamide (0.5–50 pmol) and ACEA (0.05–5 pmol) induced anxiolytic-like effects with bell-shaped dose–response curves, the higher doses being ineffective. The anandamide anxiolytic effect was potentiated by AM404 (50 pmol) and prevented by AM251 (100 pmol). Neither AM404 (0.5–50 pmol) nor AM251 (1–100 pmol) alone modified the animal behavior in the EPM. The present study suggests that the dlPAG is a possible neuroanatomical site for anxiolytic-like effects mediated by CB 1 agonists. Furthermore, this work supports the importance of neuronal uptake as a mechanism that limits the in vivo actions of anandamide.

Age-related and Non-age—related Changes in 100 Surveyed Horse Brains

Brains from 100 horses, aged 2-25 years, were systematically examined by histopathology at 46 different neuroanatomical sites. The horses were sourced from a slaughterhouse (group A, n = 57), from a kennel that collected dead animals, and from 2 diagnostic laboratories (group B, n = 43). All horses from group A and 26 horses from group B were examined by a veterinarian in the period before death. None of the horses were known to exhibit clinical signs suggestive of neurologic disease. Among the main changes identified were vacuolation in the neuropil (n = 73), neurons (n = 32), white matter (n = 31), and focal perivascular lymphoid cell infiltrates (n = 35). Spheroids were frequently seen (n = 91), and 10 horses each had more than 10 spheroids in the cuneate or gracile nucleus. Statistically significant age-related changes noted included intraneuronal (n = 97) and glial or extracellular lipofuscin deposition (n = 41), hemosiderin deposition around blood vessels (n = 60), and calcium depositions (n = 24). One horse had low-grade nonsuppurative meningoencephalitis; Alzheimer type II cells were detected in the brains of 2 horses. Hyalinized vessel walls in the cerebellum were observed in 1 horse. It was concluded that some histopathologic changes are a frequent feature in equine brains, which has implications for the pathologists involved in equine neurology and disease surveillance.

CB1Receptor Antagonism Increases Hippocampal Acetylcholine Release: Site and Mechanism of Action

Evidence indicates that blockade of cannabinoid receptors increases acetylcholine (ACh) release in brain cortical regions. Although it is assumed that this type of effect is mediated through CB1 receptor (CB1R) antagonism, several in vitro functional studies recently have suggested non-CB1R involvement. In addition, neither the precise neuroanatomical site nor the exact mechanisms underlying this effect are known. We thoroughly examined these issues using a combination of systemic and local administration of CB1R antagonists, different methods of in vivo microdialysis, CB1R knockout (KO) mice, tissue measurements of ACh, and immunochemistry. First, we showed that systemic injections of the CB1R antagonists N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR-141716A) and N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) dose-dependently increased hippocampal ACh efflux. Likewise, local hippocampal, but not septal, infusions of SR141716A or AM251 increased hippocampal ACh release. It is noteworthy that the stimulatory effects of systemically administered CB1R antagonists on hippocampal ACh release were completely abolished in CB1R KO mice. CB1R KO mice had similar basal but higher stress-enhanced hippocampal ACh levels compared with wild-type controls. It is interesting that dopamine D1 receptor antagonism counteracted the stimulatory effect of CB1R blockade on hippocampal ACh levels. Finally, immunohistochemical methods revealed that a high proportion of CB1R-positive nerve terminals were found in hippocampus and confirmed the colocalization of CB1 receptors with cholinergic and dopaminergic nerve terminals. In conclusion, hippocampal ACh release may specifically be controlled through CB1Rs located on both cholinergic and dopaminergic neuronal projections, and CB1R antagonism increases hippocampal ACh release, probably through both a direct disinhibition of ACh release and an indirect increase in dopaminergic neurotransmission at the D1 receptors.

Growing axons in fish optic nerve are accompanied by astrocytes interconnected by tight junctions

Mammalian astrocytes are in general interconnected by gap but not by tight junctions and play an ambiguous and controversially discussed role in central nervous system regeneration. At different neuroanatomical sites, fish astrocytes are interconnected by tight junctions and desmosomes and are involved in the successful regeneration of lesioned fiber tracts. In fish, newly generated retinal ganglion cells continuously grow new axons to the optic tectum but the interrelationship between glial tight junctions and axonal growth is undefined so far. We therefore investigated the occurrence of tight junctional structures and molecules within the ribbon-shaped optic nerve of a teleost fish ( Astatotilapia burtoni) and found a predominant expression of zonula occludens protein-1 and claudin-1 in astrocytes where axons of new ganglion cells are assembled retinotopically within the optic nerve. This may support a previously formulated hypothesis according to that different properties of astrocytic membranes could be responsible for different glio-neuronal interactions which in turn may determine the micro-environmental conditions of growing axons.

Addiction and its brain science

To illustrate how modern neurobiological approaches will help to identify the neurocircuits and genes involved in addictive behavior. The current disorder concept of addiction includes neurobiological foundations and neurobiological research assuming irreversible molecular and structural changes within the brain dopamine reinforcement system, constituting the 'molecular and structural switch' from controlled drug intake to compulsive drug abuse. However, those irreversible changes have not so far been identified and it is suggested that in addition to the mesolimbic dopamine system, other brain systems including the mesocortical and nigrostriatal pathways as well as their non-dopaminergic feedback-loops might be involved in addictive behavior. NEUROBIOLOGICAL APPROACH: A three-step neurobiological approach is described that allows in a first step via novel animal models and imaging techniques to identify the neuroanatomical sites mediating voluntary drug intake, reinstatement of drug-seeking behavior, relapse, loss of control and drug intake despite negative consequences. In a subsequent step, forward genetic approaches including quantitative trait loci (QTL)-analysis and gene expression profiling are helpful in identifying so-called candidate genes. In a final step, conditional animal mutants and selective pharmacological tools are used to functionally validate candidate genes. Following this validation process, the transfer to the human situation has to be made and candidate genes have to be verified further in well-phenotyped cohorts of addicted patients. This three-step neurobiological approach, that must involve an interdisciplinary team including experimental psychologists, geneticists, molecular biologists and finally clinical addiction researchers, will allow us to understand where and how the addicted brain goes awry.

Brain imaging research on subjective responses to psychotropic drugs

Neuroimaging studies on subjective responses to psychotropic drugs in humans were reviewed to examine progress in the field and identify gaps in knowledge. An exhaustive search of computerized databases identified two categories of in vivo imaging studies: i) correlates of negative(dysphoric) subjective responses to neuroleptic use in schizophrenia, and ii) research on positive (euphoric) subjective responses, mostly from substance abuse population. Research has been largely confined to neurochemical imaging of dopamine in the striatal complex, confirming earlier speculations that impaired or deficient dopaminergic function is associated with dysphoric responses, and enhanced activity is associated with euphoric or pleasurable responses. Cerebral blood flow, regional metabolic rate and glucose utilization studies provided preliminary clues to the putative neuroanatomical sites. Neuroimaging techniques added credibility to the study of subjective responses; however, further studies are required to identify the underlying anatomical and neurochemical interactions in order to enhance their applied value.

Neural and Endocrine Correlates of Sadness In Women: Implications for Neural Network Regulation of HPA Activity

In order to evaluate the suprahypothalamic neuroanatomical sites of relevance to adrenocorticotropic hormone (ACTH) and cortisol regulation, single photon emission computed tomography (SPECT) investigation of induced sadness was combined with a linear regression analysis of these hormone levels during mood induction. Images from eight healthy women were analyzed by statistical parametric mapping (SPM), replicating many findings from prior sadness induction studies. Statistical parametric mapping endocrine covariate analysis showed that the ventromedial prefrontal, anterior cingulate, and insular cortices may regulate ACTH and the insular cortex may be related to regulation of cortisol during sadness. Dysfunction of these sites may contribute to the cortisol dysregulation observed in some subjects with major depression.

Neural and Endocrine Correlates of Sadness In Women: Implications for Neural Network Regulation of HPA Activity

In order to evaluate the suprahypothalamic neuroanatomical sites of relevance to adrenocorticotropic hormone (ACTH) and cortisol regulation, single photon emission computed tomography (SPECT) investigation of induced sadness was combined with a linear regression analysis of these hormone levels during mood induction. Images from eight healthy women were analyzed by statistical parametric mapping (SPM), replicating many findings from prior sadness induction studies. Statistical parametric mapping endocrine covariate analysis showed that the ventromedial prefrontal, anterior cingulate, and insular cortices may regulate ACTH and the insular cortex may be related to regulation of cortisol during sadness. Dysfunction of these sites may contribute to the cortisol dysregulation observed in some subjects with major depression.

Neurobiology and neuroimmunology of Tourette's syndrome: an update.

Tourette's syndrome is a childhood-onset neuropsychiatric disorder characterized by the presence of both multiple motor and vocal tics. While the pathogenesis at a molecular and cellular level remains unknown, structural and functional neuroimaging studies point to the involvement of the basal ganglia and related cortico-striato-thalamo-cortical circuits as the neuroanatomical site for Tourette's syndrome. Moreover, Tourette's syndrome has a strong genetic component, and considerable progress has been made in understanding the mode of transmission and in identifying potential genomic loci. Summaries of recent findings in these areas will be reviewed, followed by a critical overview of findings both supporting and challenging the proposed autoimmune hypothesis of Tourette's syndrome. We conclude that Tourette's syndrome is a heterogeneous disorder, and that immune factors may indeed be involved in some patients.

Biphasic Effects of Cannabinoids on Acetylcholine Release in the Hippocampus: Site and Mechanism of Action

Cannabinoids have been shown to critically modulate cholinergic neurotransmission in the hippocampus, yet opposing effects of cannabinoid receptor 1 (CB1R) agonists on hippocampal synaptic acetylcholine (ACh) efflux have been reported. This study shows that administration of a synthetic CB1R agonist results in a biphasic, dose-dependent, effect on hippocampal ACh: a low (0.5 mg/kg, i.p.) and a high (5 mg/kg, i.p) dose of WIN55,212-2 induces a transient stimulation and a prolonged inhibition of hippocampal ACh efflux, respectively. Both effects of WIN55,212-2 are mediated through CB1 receptors coupled to Gi but involve different neuroanatomical sites. Thus, intrahippocampal infusion of the CB1R antagonist SR141716A or pertussis toxin blocked the inhibition of hippocampal ACh release induced by the high dose of WIN55,212-2, but was without effect on the stimulatory action of the low dose. In contrast, this latter effect was blocked by SR141716A or pertussis toxin infused, in dual microdialysis experiments, in the septum, in which the majority of cholinergic cell bodies projecting to the hippocampus reside. The stimulatory and inhibitory effects of WIN55,212-2 on hippocampal ACh involve dopamine D1 and D2 receptor activation, respectively, given that pretreatment with D1 and D2 receptor antagonists prevents the respective actions of WIN55,212-2. We propose that the in vivo observed biphasic effects of CB1R agonists on hippocampal ACh release result from a differential, functional association of anatomicaly distinct subpopulations of CB1-Gi coupled receptors to neurotransmitter systems that have opposing effects on ACh release. This concept could provide a theoretical framework to understand endocannabinoids as state-dependent modulators of neuronal activity.

Differences in neuroanatomical sites of apoD elevation discriminate between schizophrenia and bipolar disorder.

We previously demonstrated that apolipoprotein D (apoD) levels are elevated in the dorsolateral prefrontal cortex and caudate obtained postmortem from subjects with schizophrenia and bipolar disorder compared to controls, suggesting a focal compensatory response to neuropathology associated with psychiatric disorders. We have now extended those studies by measuring apoD protein levels in additional brain regions from post-mortem samples of schizophrenic and bipolar disorder subjects using an enzyme-linked immunosorbent assay. Increased apoD levels were observed in the lateral prefrontal cortex (Brodmann Area 46) in both schizophrenia (46%) and bipolar disorder (111%), and in the orbitofrontal cortex (Brodmann Area 11) (44.3 and 37.9% for schizophrenia and bipolar disorder, respectively). However, differences between the disease groups were observed in other brain regions. In subjects with schizophrenia, but not bipolar disorder, apoD levels were significantly elevated in the amygdala (42.8%) and thalamus (31.7%), while in bipolar disorder, but not schizophrenia, additional increases were detected in the parietal cortex (Brodmann Area 40; 123%) and the cingulate cortex (Brodmann Area 24; 57.7%). These data demonstrate that there is anatomical overlap in the pathophysiologies of schizophrenia and bipolar disorder, as well as areas of pathology that distinguish the two disorders.

Analysis of lexical-semantic processing and extensive neurological, electrophysiological, speech perception, and language evaluation following a unilateral left hemisphere lesion: Pure word deafness?

Background : Theoretical models of lexical-semantic processing that explicate the relationships between spoken word comprehension, repetition, and writing to dictation are discussed in relation to pure word deafness (PWD). Various theories relative to the neuroanatomical sites and pathophysiological/electrophysiological mechanisms that cause the speech perception deficit seen in PWD are reviewed, as well as case studies that have identified variables that facilitate comprehension of spoken language for individuals with PWD. Aims : A case study of an individual with an extensive and complex neurological history and a constellation of symptoms suggestive of PWD is presented. Extensive evaluation, including experimental tasks developed to test a theoretical lexical processing model, was undertaken to determine whether this case fitted the criteria for a diagnosis of PWD. Methods & Procedures : Extensive neurological, electrophysiological, speech perception, and language testing was undertaken to confirm site of lesion, assess neurophysiological processes underlying speech perception, and determine overall language status. Experimental tasks based on a lexical-semantic processing model assessed word and nonword repetition and writing to dictation under two conditions: presentation with and without facial cues. Outcomes & Results : MRI confirmed a lesion in the participant's left frontoparietal area. Electrophysiological measures indicated his auditory nerve and auditory brainstem functions were intact, middle latency response (MLR) was normal over his right hemisphere and absent over his left hemisphere, and a significant mismatch negativity (MMN) response was elicited by pitch, but not phonetic, differences. Speech perception testing indicated he had difficulty with spectral or spectro-temporal discrimination and combining phonological and semantic information, as well as decreased ability to use formant motion in sentence perception and to perceive speech in noise. Language testing revealed relatively intact spontaneous language production and reading comprehension. The participant's performance on experimental tasks indicated an effect of syllable length and presentation mode for both words and nonwords. That is, as the number of syllables increased, his performance decreased; however, repetition and writing to dictation reflected superior performance with facial cues regardless of word and nonword length when compared to presentation without cues. Relative to the lexical processing model, the participant's performance suggested impoverished phonetic processing in the auditory analysis system. Conclusions : The results of extensive evaluation revealed a selective impairment in acoustic phonetic perception that is consistent with a diagnosis of PWD. The findings of this study support other studies that have demonstrated that speech perception involves cortical areas other than the temporal lobes.